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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2009 May 18;27(19):3198–3204. doi: 10.1200/JCO.2008.20.6110

Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Christian Langer 1, Guido Marcucci 1,, Kelsi B Holland 1, Michael D Radmacher 1, Kati Maharry 1, Peter Paschka 1, Susan P Whitman 1, Krzysztof Mrózek 1, Claudia D Baldus 1, Ravi Vij 1, Bayard L Powell 1, Andrew J Carroll 1, Jonathan E Kolitz 1, Michael A Caligiuri 1, Richard A Larson 1, Clara D Bloomfield 1
PMCID: PMC2716941  PMID: 19451432

Abstract

Purpose

To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods

MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials.

Results

Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation.

Conclusion

MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.

INTRODUCTION

Nonrandom cytogenetic abnormalities are among the most important prognostic factors in acute myeloid leukemia (AML).14 However, approximately 45% of adults younger than 60 years of age with primary AML have cytogenetically normal (CN) disease at diagnosis and thus lack informative chromosome markers for risk stratification.14 Recently, this large cytogenetic group was shown to be composed of subsets differing for the presence of distinct submicroscopic genetic alterations.5

The meningioma 1 (MN1) gene is located at chromosome band 22q12 and encodes a protein that participates in a gene transcription regulator complex with the nuclear receptor RAR-RXR or the vitamin D receptor.6,7 The involvement of this gene in human neoplasia was initially discovered in a case of meningioma carrying t(4;22)8 and also found in myeloid malignancies with t(12;22).9 High levels of MN1 expression were recently associated with inv16 AML,10 and shown, in a mouse model, to cooperate with CBFB-MYH11 gene fusion in the development of AML.11 However, the mechanisms through which aberrant expression of MN1 contributes to malignant transformation remain to be elucidated.12,13

Recently, Heuser et al14 reported that overexpression of MN1 predicted worse outcome in CN-AML patients. To date, however, these results have not been independently corroborated or tested in the context of several other established prognostic markers in CN-AML. Thus, to validate MN1 expression's prognostic importance in CN-AML, we measured the MN1 expression in diagnostic bone marrow (BM) samples from younger adult CN-AML patients that were also comprehensively characterized for other molecular markers associated with outcome. Furthermore, to gain insight into MN1-mediated leukemogenesis, we derived gene- and microRNA-expression signatures associated with changes in MN1 expression levels.

PATIENTS AND METHODS

Patients, Treatment, Cytogenetic, and Molecular Analyses

One hundred nineteen adults younger than 60 years of age with untreated, primary CN-AML with material available for analyses were included. Patients were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 (n = 38) and 19808 (n = 81) with intensive induction chemotherapy and consolidation with autologous peripheral blood stem cell transplantation (SCT; Appendix, online only).15,16 No differences in outcome (complete remission rate [CR], P = .86; disease-free survival [DFS], P = .37; overall survival [OS], P = .33) were observed between the patients studied for MN1 expression and the remaining CN-AML patients not included (n = 121).

Pretreatment BM cytogenetic analyses were performed by CALGB-approved institutional cytogenetic laboratories on CALGB 8461, a prospective cytogenetic companion, and centrally reviewed.17 MN1 copy numbers normalized to ABL copy numbers were measured in BM samples by real-time reverse transcriptase polymerase chain reaction quantification (Appendix). The presence or absence of additional molecular markers such as FLT3 internal tandem duplication (FLT3-ITD),18,19 FLT3 tyrosine kinase domain mutations (FLT3-TKD),20,21 mutations in the NPM1,22 CEBPA,23 and WT124 genes, MLL partial tandem duplication (MLL-PTD),25,26 and ERG27,28 and BAALC29,30 expression levels were assessed centrally. All patients gave informed consent for the research use of their specimens, in accordance with the Declaration of Helsinki.

Gene-Expression and MicroRNA-Expression Profiling

RNA samples from 75 of 81 patients studied for MN1 expression enrolled on CALGB 19808 were analyzed for genome-wide gene expression using Affymetrix U133 plus 2.0 GeneChips (Affymetrix, Santa Clara, CA), as previously reported (Appendix).10,31

Of the 75 samples analyzed for genome-wide gene expression, 73 were also analyzed for genome-wide microRNA expression. Biotinylated first strand cDNA from total RNA extracted from pretreatment BM or blood mononuclear cell samples was synthesized using biotin-labeled random octamer primers and was hybridized onto microRNA microarray chips, as previously reported.32 Images of the microRNA microarrays were acquired as previously reported.33

Statistical Methods

The main objective was to evaluate the impact of MN1 expression on clinical outcome. We defined CR as BM cellularity ≥ 20% and fewer than 5% blasts, and recovery of leukocyte (≥ 1,500/μL) and platelet (> 100,000/μL) counts; relapse as ≥ 5% of BM, leukemic blasts, circulating blasts, or extramedullary leukemia; DFS as the interval from CR achievement until relapse or death, regardless of cause; OS as the date on study until death. Patients alive at last follow-up were censored for both DFS and OS. MN1 expression values were calculated as the natural log transformation of the normalized MN1 copy numbers; this continuous variable was used for all statistical analyses. Pretreatment CNS, spleen, liver, skin, nodes, gum, or mediastinal mass involvement constituted extramedullary disease.

The associations of MN1 expression with baseline clinical, demographic, and molecular features, and achievement of CR were analyzed using one-way analysis of variance. Kaplan-Meier plots were generated for each time-to-event outcome measure (DFS and OS) using MN1 expression quartiles. The corresponding tests for trend were calculated for each survival end point.34 Comparisons between cases analyzed for MN1 v those not analyzed were tested using the Fisher's exact test for CR rates and the log-rank test for the OS and DFS end points.

Multivariable logistic regression models were constructed to analyze factors related to the probability of achieving CR and multivariable Cox proportional hazards models were constructed to analyze factors important for the survival end points, OS and DFS. Factors examined for model inclusion were MN1 expression, FLT3-ITD, FLT3-TKD, NPM1 and WT1 mutational status, age, hemoglobin, platelet count, WBC, percentages of BM and blood blasts, sex, race, and extramedullary involvement, and for survival end points only, MLL-PTD, CEBPA mutational status, and ERG and BAALC expression levels. For the multivariable Cox models, the proportional hazards assumption was checked for each variable individually. If the proportional hazards assumption was not met for a particular variable for a given end point, an artificial time-dependent covariate was included in the model for that end point. Variables considered for inclusion in the logistic and Cox multivariable models were those significant at α = .20 from the univariable models. All models were constructed using a limited backwards selection procedure. Variables remaining in the final models were significant at α = .05. For achievement of CR, estimated odds ratios (OR), and for survival end points, hazard ratios (HR) with their corresponding 95% CIs were obtained for each significant prognostic factor.

For microarray analyses, summary measures of gene and microRNA expression were computed, normalized, and filtered (Appendix).35 Pearson correlation coefficients were computed between the resulting expression values of 24,183 Affymetrix probe sets and the natural log transformation of MN1 expression, and between the resulting expression values of 305 microRNA probes and the natural log transformation of MN1 expression values; significant Affymetrix probe sets (P < .001) and microRNA probes (P < .005) comprised the MN1 gene- and microRNA-expression signatures, respectively. GenMAPP version 2.1 and MAPPFinder version 2.136 (Gladstone Institutes, the University of California, San Francisco, CA; http://www.genmapp.org/) were used to assess over-represented gene ontology (GO) terms within the identified gene-expression signature (Appendix).

All statistical analyses were performed by the CALGB Statistical Center.

RESULTS

Association of MN1 Expression With Molecular and Clinical Characteristics and Outcome

At diagnosis, higher MN1 expression (MN1/ABL copy number range, 0.007 to 7.317) was associated with lower frequency of NPM1 mutations (P < .001) and higher BAALC expression (P = .004) and less extramedullary disease (P = .01; Table 1; Fig 1). No other molecular or clinical characteristics were significantly associated with MN1 expression.

Table 1.

Relationship of Clinical and Molecular Characteristics With MN1 Expression Levels in Patients With Cytogenetically Normal Acute Myeloid Leukemia at Diagnosis (N = 119)

Characteristic Summary Statistics
P *
No. %
Median age, years 43 .64
    Range 18-59
Sex .52
    Female 62 52
    Male 57 48
Race .15
    White 104 88
    Nonwhite 14 12
Median hemoglobin, g/L 92 .21
    Range 48-136
Median platelet count, ×109/L 55 .78
    Range 8-395
Median WBC, ×109/L 27.3 .94
    Range 1.4-273.0
Median blood blasts, % 59 .78
    Range 0-95
Median bone marrow blasts, % 67 .20
    Range 21-99
Extramedullary involvement .01
    No 85 72
    Yes 33 28
FLT3-ITD .30
    Negative 66 55
    Positive 53 45
FLT3-TKD .06
    Negative 109 92
    Positive 10 8
NPM1 < .001
    Wild-type 39 33
    Mutated 80 67
CEBPA .15
    Wild-type 97 83
    Mutated 20 17
ERG expression .86
    Low 50 56
    High 39 44
BAALC expression .004
    Low 46 50
    High 46 50
WT1 .23
    Wild-type 101 90
    Mutated 11 10
MLL-PTD .81
    Negative 111 93
    Positive 8 7

NOTE. Not all 119 patients were evaluated for all the molecular markers. For each molecular marker, the number of patients negative or positive, wild-type or mutated or low or high is reported in the Summary Statistics column.

Abbreviations: FLT3-ITD, internal tandem duplication of the FLT3 gene; FLT3-TKD, tyrosine kinase domain mutation of the FLT3 gene; MLL-PTD, partial tandem duplication of the MLL gene.

*

P values are from the one-way analysis of variance overall F-test, evaluating the presence of any linear relationship between the MN1 expression and the variable tested. For tests with a P value < .20, the characteristic associated with higher MN1 expression appears in bold.

Fig 1.

Fig 1.

Clinical and molecular variables significantly associated with the meningioma 1 (MN1) gene expression. The direction of the correlation is shown by displaying the mean values and corresponding 95% CIs of MN1 expression for each category of the clinical and molecular variables.

The overall CR rate of the patients analyzed for MN1 expression was 83%. Patients who failed to achieve CR had higher MN1 levels (P = .006; Fig 2A). No interaction between MN1 levels and induction treatment (ie, with or without PSC-833) was found for CR achievement. On multivariable analysis, patients with higher MN1 expression were less likely to achieve CR (P = .005) after adjustment for WBC (P = .005; Table 2).

Fig 2.

Fig 2.

Outcome of cytogenetically normal acute myeloid leukemia (CN-AML) patients according to the meningioma 1 (MN1) gene expression levels. (A) Comparison of MN1 expression in patients who achieved a complete remission (CR) compared with patients who did not achieve a CR. The direction of the correlation is shown by displaying the mean MN1 expression and corresponding 95% CIs. (B) Disease-free survival of CN-AML patients according to quartile value of MN1 expression levels. CR rates for each quartile are as follows: 90%, 97%, 77%, 69% for Q1, Q2, Q3, Q4, respectively. (C) Overall survival of CN-AML patients according to quartile value of MN1 expression levels. For display purposes, MN1 expression was treated as a categoric variable (patients were grouped according to the MN1 copy quartiles from the lowest [quartile 1] to the highest [quartile 4] and Kaplan-Meier plots were generated). P values evaluate the trend in survival across MN1 expression quartiles.

Table 2.

Multivariable Analyses for Clinical Outcome

Variables in Final Model by End Point HR/OR 95% CI P
CR*
    MN1 expression 0.54 0.35 to 0.83 .005
    WBC 0.52 0.33 to 0.82 .005
DFS
    MN1 expression 1.35 1.06 to 1.72 .01
    WT1, mutated v wild-type 3.16 1.28 to 7.81 .01
    FLT3-ITD, positive v negative 2.18 1.03 to 4.61 .02
    ERG expression, high v low 1.99 1.03 to 3.84 .04
OS§
    MN1 expression 1.27 1.01 to 1.58 .04
    WT1, mutated v wild-type 6.00 2.80 to 12.86 < .001
    NPM1, wild-type v mutated 2.23 1.04 to 4.76 .04
    FLT3-ITD, positive v negative 2.70 1.41 to 5.17 .01
    WBC 1.75 1.34 to 2.28 < .001

NOTE. ORs < 1.0 mean lower CR rate for the higher values of the continuous variables. HRs > 1.0 indicate higher risk for an event for the higher values of the continuous variables and the first category listed for the categorical variables.

Abbreviations: CR, complete remission; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; OR, odds ratio; MN1, natural log transformation of normalized MN1 copy numbers; WBC, white blood count in 50 unit increments; FLT3-ITD, internal tandem duplication of the FLT3 gene.

*

Variables considered in the model based on univariable analyses were MN1, FLT3-ITD (positive v negative), age, hemoglobin, WBC (50 unit increments), and race.

Variables considered in the model based on univariable analyses were MN1, ERG expression (high v low), WT1 (mutated v wild-type), FLT3-ITD (positive v negative), WBC (50 unit increments), race, and NPM1 (wild-type v mutated).

Does not meet the proportional hazards assumption. For DFS, the hazard ratio for FLT3-ITD is reported at 9 months (was not significant after this time point). for OS, the hazard ratio for WT1 is reported at 9 months (not significant before this time point), FLT3-ITD is reported at 1 year (not significant after this time point).

§

Variables considered in the model based on univariable analyses were MN1, ERG expression (high v low), FLT3-ITD (positive v negative), WT1 (mutated v wild-type), BAALC expression (high v low), WBC (50 unit increments), age, hemoglobin, percentage of blood blasts, extramedullary involvement, and NPM1 (wild-type v mutated).

The median follow-up for patients with no event (ie, failure to achieve CR, relapse, or death) was 5.1 years (range, 2.7 to 9.9 years). Higher MN1 expression was associated with shorter DFS (P < .001) and OS (P < .001). An interaction between MN1 levels and variations in the consolidation or maintenance treatments could not be evaluated because of sample size limitations. In multivariable models, higher MN1 expression was associated with shorter DFS (P = .01) after adjusting for WT1 mutations (P = .01), FLT3-ITD (P = .02), and high ERG expression (P = .04). Likewise, shorter OS (P = .04) was associated with higher MN1 expression when controlling for WT1 (P < .001) and NPM1 mutations (P = .04), FLT3-ITD (P = .01), and WBC (P < .001; Table 2). Similar results were observed when the FLT3-ITD/FLT3 wild-type allelic ratio (no FLT3-ITD v FLT3-ITD/FLT3 wild-type < .7 v FLT3-ITD/FLT3 wild-type ≥ .7) rather than presence compared with absence of FLT3-ITD, was utilized as a factor in the multivariable models.

To graphically display the relationship between MN1 expression and clinical outcome, patients were divided into four groups corresponding to the quartile (Q) values of MN1 expression (Figs 2B, 2C). The 5-year DFS and OS estimates were progressively lower from Q1 (ie, patients with the lowest 25% of MN1 expression values) to Q4 (ie, patients with the highest 25% of MN1 expression values; P < .001, test for trend for both DFS and OS). Patients in Q1 had remarkably favorable outcomes, with expected 5-year DFS and OS rates of 74% and 80%, respectively, compared with only 36% and 40%, respectively, for the remaining patients.

Biologic Insights

To gain insight into leukemogenic mechanisms associated with changes in MN1 expression, we derived both gene- and microRNA-expression signatures using microarray assays. The MN1-associated gene-expression signature consisted of 555 probes (Appendix Table A1, online only; Fig 3). Expression of 261 probe sets positively correlated with MN1 expression levels, and expression of 294 probe sets negatively correlated with MN1 expression levels. The probe set for MN1 had the highest positive coefficient of correlation (r = .87), corroborating the quantification of MN1 expression obtained by real-time RT-PCR. Furthermore, we found MN1 expression levels to be directly correlated with BAALC expression levels and with the expression of genes recently reported as associated with a BAALC expression signature,30 specifically, PROM1, CD34, FZD6, CRYGD, CD200, and ABCB1 (MDR1). MN1 expression levels were negatively associated with expression of HOX genes (ie, HOXA2, HOXA3, HOXA4, HOXA5, and MEIS1) that have also been reported to be expressed at lower levels in NPM1 wild-type patients.37 Thus, the microarray data were consistent with the association between higher MN1 levels and high BAALC expresser and NPM1 wild-type status observed at diagnosis in our patients (Table 1; Fig 1).

Fig 3.

Fig 3.

Heat map of gene probe sets that correlated significantly with the meningioma 1 (MN1) gene expression. Expression values of the probe sets are represented by color, with green indicating expression below and red expression above the median value for the given probe set. For display purposes, the expression values of the probe sets were centered so that each probe set has the same median expression value. Rows represent probe sets and columns represent patients. Patients are ordered according to MN1 expression levels measured by real-time reverse transcriptase polymerase chain reaction.

Using GO (www.geneontology.org), a project that groups together genes (referred to as members) participating in specific biologic processes (referred to as terms), we tested separately which terms were over-represented among the genes positively and negatively correlated with MN1 expression levels. An over-represented term is one for which more members assigned to that term are found in the microarray signature than expected by chance. Thus, over-represented terms may provide insight into the biologic functions of the gene-expression signature associated with MN1 expression changes. Sixteen GO terms were over-represented among the 261 gene probes positively correlated with MN1 expression (Appendix Table A2, online only). Most of the 16 GO terms were related to the macrophage immune function of antigen processing and presentation.38 Twenty-nine GO terms were over-represented among the 294 probe sets that negatively correlated with MN1 expression (Appendix Table A2). Among those 29 GO terms, most were related to DNA, chromatin or chromosome organization, and tissue and organ development.

We derived an MN1-associated microRNA-expression signature comprising 15 microRNAs (Appendix Table A3, online only; Fig 4). Of the 15 microRNA probes, expression of 8 was positively and expression of 7 negatively correlated with MN1 expression. Five of 8 microRNA probes positively associated with MN1 expression corresponded to the hsa-miR-126 family (including both hsa-miR-126 and hsa-miR-126*). This microRNA family was recently reported to enhance the proangiogenic activity of VEGF and regulate new blood vessel formation.39,40 We also noted upregulation of hsa-miR-424, a regulator of monocyte and macrophage differentiation.41 Among the microRNA probes negatively correlated with MN1, we found microRNAs involved in apoptosis (ie, hsa-miR-16)42 or malignant transformation (ie, hsa-miR-19a and hsa-miR-20a members of the miR-17-92 polycistron)43,44 in addition to other microRNAs with unknown gene targets (ie, hsa-miR-100 and hsa-miR-196a).

Fig 4.

Fig 4.

Heat map of microRNA probes that correlated significantly with the meningioma 1 (MN1) gene expression. Expression values of the probes are represented by color, with green indicating expression below and red expression above the median value for the given probe, and gray indicating a missing value. For display purposes, the expression values of the probes were centered so that each probe has the same median expression value. Rows represent probes and columns represent patients. Patients are ordered according to MN1 expression levels measured by real-time reverse transcriptase polymerase chain reaction.

DISCUSSION

High levels of MN1 expression were recently reported to negatively impact on outcome of CN-AML patients.14 To our knowledge, these results have not yet been independently validated. Thus, we tested the prognostic value of MN1 expression levels in younger CN-AML patients enrolled on similar CALGB first-line treatment protocols. We showed that the levels of MN1 expression directly correlated with the risk of failing remission induction chemotherapy, relapse, and/or death, and predicted outcome independently of other clinical and molecular variables, thereby confirming the initial observation by Heuser et al.14 All patients survived ≥ 30 days and were assessable for disease response after treatment. Therefore, the value of MN1 expression to predict treatment-related mortality was not assessed.

The two studies presented several methodologic differences. We analyzed exclusively patients diagnosed with primary AML, whereas Heuser et al14 also included patients with secondary AML. The patients in our study were similarly treated on two CALGB protocols that included consolidation treatment with autologous SCT (ASCT) or, in those few cases where ASCT was not possible, intensive consolidation chemotherapy. Patients who underwent allogeneic SCT in first CR were excluded. The German study included patients who underwent allogeneic SCT in addition to those receiving consolidation with ASCT or intensive chemotherapy.14 In the German study,14 MN1 expression levels were measured using both BM and blood samples, and comparison of outcome was performed between higher and lower MN1 expressers, dichotomized at the median value of MN1 expression. In our study, only BM samples were analyzed, and we considered MN1 expression as a continuous variable to avoid the need to adjust for different tissue types and eliminate the necessity of choosing arbitrary cutoff values to define groups of patients for comparison. Finally, Heuser et al14 analyzed patients only for FLT3-ITD, FLT3-TKD, MLL-PTD, and NPM1 mutations along with MN1 expression. In addition to these molecular markers, we also analyzed WT1 and CEBPA mutations, and ERG and BAALC expression levels. Despite these differences, the two studies were remarkably similar in their conclusions regarding the association of higher MN1 levels with wild-type NPM1 and poor outcome. However, while Heuser et al14 showed that MN1 expression was the only molecular marker that remained predictive of outcome in the final bivariable and multivariable models, we found that MN1 expression provided prognostic information additional to that provided by FLT3-ITD and WT1 mutations (for DFS and OS), high ERG expression (for DFS), and NPM1 mutations (for OS).

Previous studies reported MN1 as a fusion partner in the MN1/ETV6 chimeric gene in t(12;22), and to be overexpressed in inv16 AML.11,12 MN1 overexpression was shown to confer resistance to the differentiation activity of all-trans-retinoic acid (ATRA) in AML.13 Although murine models have in part recapitulated the ATRA-resistant phenotype of human MN1-associated AML, little is known about the mechanism through which aberrant expression of MN1 drives myeloid leukemogenesis.11,13 Thus, to gain insight into the functional significance of MN1 expression in AML, we derived gene and microRNA profiles that correlated with MN1 expression levels.

The gene-expression signature associated with MN1 expression comprised 555 probes. Notably, BAALC was among genes that correlated most strongly with MN1 expression. At diagnosis, high BAALC expressers indeed had higher levels of MN1 expression (Table 1; Fig 1). Consistent with this finding, we observed similarities between a signature associated with BAALC expression that we recently reported30 and the signature associated with MN1 expression. Associated with higher MN1 and BAALC expression were PROM1, CD34, FZD6, and CRYGD (genes expressed in noncommitted hematopoietic precursors), CD200 (associated with poor outcome in AML), and ABCB1 (involved in chemoresistance). Furthermore, in a comparative GO analysis (not shown), eight GO terms related to DNA, chromatin, and chromosome assembly, and organization were over-represented among the genes downregulated in both the BAALC and MN1 gene-expression signatures. These findings suggest a potential functional interplay between MN1 and BAALC in their contribution to myeloid leukemogenesis.

Despite the aforementioned similarities, the leukemogenic mechanisms associated with aberrant expression of MN1 and BAALC are unlikely to be identical. Using GO analysis, we showed that genes involved in antigen processing and presentation were positively associated with the MN1, but not BAALC, gene-expression signature. Among those, there were genes encoding both MHC class I and class II proteins and CD74 that are central to the mechanisms of antigen processing and presentation for T-cell activation by macrophage and dendritic cells.38 Interestingly, higher MN1 expression was also associated with higher expression of hsa-miR-424, which is transactivated by SPI1 (PU.1) and upregulated during monocyte/macrophage differentiation.41 We have recently published data suggesting that overexpression of certain microRNAs that potentially target genes encoding Toll-like receptors and IL1B, which also participate in macrophage and dendritic cell activation, are associated with worse prognosis.33 Altogether, these data suggest that aberrant activation of mechanisms involved in both native and acquired immunologic response may play a role in sustaining myeloblast proliferation and survival.

Among the eight microRNA probes whose higher expression was associated with higher MN1 expression, five corresponded to miR-126 family members. hsa-miR-126 and hsa-miR-126* are generated from the splicing and processing of intron 7 of the EGFL7 gene.40,45 Consistent with these data, we observed that MN1 expression positively correlated with expression of both EGFL7 and hsa-miR-126. A leukemogenic role for hsa-miR-126 has hitherto not been reported. However, two recent studies have shown that hsa-miR-126 regulates vascular integrity and angiogenesis by repressing negative regulators of the VEGF pathways.39,40 Whether aberrant activation of these mechanisms can contribute to leukemogenesis and impact the treatment response and outcome of CN-AML patients remains to be determined. Finally, since hsa-miR-16 targets the antiapoptotic BCL2 gene and is downregulated in cancer patients with poor outcome,42 it is not surprising that lower hsa-miR-16 expression was associated with higher MN1 expression predicting treatment resistance and worse outcome. It was somewhat surprising, however, that lower expression levels of hsa-miR-19a and hsa-miR-20, both part of the hsa-miR17-92 cluster, were associated with higher MN1 levels as this cluster was previously reported to be overexpressed in aggressive neoplasms (ie, B-cell lymphoma and lung cancer) and function as an oncogene.43,44

In summary, we show that higher MN1 expression is associated with wild-type NPM1, higher BAALC expression and worse outcome in CN-AML independent of other prognostic molecular markers. Patients with higher MN1 expression appear to share biologic features with patients with higher BAALC expression, namely upregulation of genes involved in chemoresistance in noncommitted hematopoietic precursors, and/or those with wild-type NPM1 (ie, lower expression of HOX genes). Aberrant MN1 expression seemingly contributes to leukemogenesis by affecting mechanisms of monocytic/macrophage function and differentiation. Validation of these findings in preclinical models and larger clinical studies may lead to the designing of novel therapies targeting activation of these potentially leukemogenic mechanisms by MN1 overexpression.

Supplementary Material

[Data Supplement]

Appendix

The following Cancer and Leukemia Group B institutions, principal investigators, and cytogeneticists participated in this study: The Ohio State University Medical Center, Columbus, OH: Clara D. Bloomfield, Karl S. Theil, and Nyla A. Heerema (grant no. CA77658); North Shore–Long Island Jewish Health System, Manhasset, NY: Daniel R. Budman and Prasad R.K. Koduru (grant no. CA35279); Wake Forest University School of Medicine, Winston-Salem, NC: David D. Hurd, Wendy L. Flejter, and Mark J. Pettenati (grant no. CA03927); Washington University School of Medicine, St Louis, MO: Nancy L. Bartlett, Michael S. Watson, and Jaime Garcia-Heras (grant no. CA77440); University of Massachusetts Medical Center, Worcester, MA: William W. Walsh, Vikram Jaswaney, Michael J. Mitchell, and Patricia Miron (grant no. CA37135); Roswell Park Cancer Institute, Buffalo, NY: Ellis G. Levine and AnneMarie W. Block (grant no. CA02599); Eastern Maine Medical Center, Bangor, ME: Harvey M. Segal and Laurent J. Beauregard (grant no. CA35406); University of Puerto Rico School of Medicine, San Juan, Puerto Rico: Eileen I. Pacheco, Leonard L. Atkins, Cynthia C. Morton, and Paola Dal Cin; Dana-Farber Cancer Institute, Boston, MA: Eric P. Winer, Paola Dal Cin, and Cynthia C. Morton (grant no. CA32291); Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff and Thuluvancheri K. Mohandas (grant no. CA04326); Duke University Medical Center, Durham, NC: Jeffrey Crawford and Mazin B. Qumsiyeh (grant no. CA47577); University of Chicago Medical Center, Chicago, IL: Gini Fleming, Diane Roulston, Katrin M. Carlson, Yanming Zhang, and Michelle M. Le Beau (grant no. CA41287); University of Iowa Hospitals, Iowa City, IA: Gerald H. Clamon and Shivanand R. Patil (grant no. CA47642); University of North Carolina, Chapel Hill, NC: Thomas C. Shea and Kathleen W. Rao (grant no. CA47559); University of California at San Diego: Barbara A. Parker, Renée Bernstein, and Marie L. Dell'Aquila (grant no. CA11789); Christiana Care Health Services Inc, Newark, DE: Stephen S. Grubbs and Jeanne M. Meck (grant no. CA45418); Ft Wayne Medical Oncology/Hematology, Ft Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; Georgetown University Medical Center, Washington, DC: Minnetta C. Liu and Jeanne M. Meck (grant no. CA77597); Massachusetts General Hospital, Boston, MA: Jeffrey W. Clark, Paola Dal Cin, and Cynthia C. Morton (grant no. CA 12,449); Rhode Island Hospital, Providence, RI: William Sikov, Shelly L. Kerman, and Aurelia Meloni-Ehrig (grant no. CA08025); State University of New York Upstate Medical University, Syracuse, NY: Stephen L. Graziano and Constance K. Stein (grant no. CA21060); Virginia Commonwealth University Minority Based Community Clinical Oncology Program, Richmond, VA: John D. Roberts and Colleen Jackson-Cook (grant no. CA52784); Weill Medical College of Cornell University, New York, NY: John Leonard, Prasad R.K. Koduru, and Andrew J. Carroll (grant no. CA07968); Western Pennsylvania Hospital, Pittsburgh, PA: John Lister and Gerard R. Diggans; Vermont Cancer Center, Burlington, VT: Hyman B. Muss and Mary Tang (grant no. CA77406); Long Island Jewish Medical Center CCOP, Lake Success, NY: Kanti R. Rai and Prasad R.K. Koduru (grant no. CA11028); Medical University of South Carolina, Charleston, SC: Mark R. Green and G. Shashidhar Pai (grant no. CA03927); Minneapolis VA Medical Center, Minneapolis, MN: Vicki A. Morrison and Sugandhi A. Tharapel (grant no. CA47555); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant no. CA04457); Nevada Cancer Research Foundation CCOP, Las Vegas, NV: John A. Ellerton and Marie L. Dell'Aquila (grant no. CA35421); University of California at San Francisco: Charles J. Ryan and Kathleen E. Richkind (grant no. CA60138); University of Illinois at Chicago: David J. Peace and Maureen M. McCorquodale (grant no. CA74811); University of Minnesota, Minneapolis, MN: Bruce A. Peterson and Betsy A. Hirsch (grant no. CA16450); University of Nebraska Medical Center, Omaha, NE: Anne Kessinger and Warren G. Sanger (grant no. CA77298); Walter Reed Army Medical Center, Washington, DC: Brendan M. Weiss and Digamber S. Borgaonkar (grant no. CA26806).

Treatment

Patients enrolled in Cancer and Leukemia Group B (CALGB) study 19808 were randomly assigned to receive induction chemotherapy with cytarabine, daunorubicin, and etoposide with or without PSC-833 (valspodar), a multidrug resistance protein inhibitor (Kolitz JE, George SL, Marcucci G, et al: Blood 106:122a-123a, 2005 [abstr 407]). On achievement of complete remission (CR), patients were assigned to intensification with high-dose cytarabine and etoposide for stem cell mobilization followed by myeloablative treatment with busulfan and etoposide supported by autologous peripheral blood stem cell transplantation. Patients enrolled in CALGB 9621 were treated similarly to those in CALGB 19808, as previously reported (Kolitz JE, George SL, Dodge RK, et al: J Clin Oncol 22:4290-4301, 2004). The only difference was that CALGB 9621 tested dose escalation of daunorubicin and etoposide during induction treatment, whereas the doses of these drugs were the same for all patients enrolled onto CALGB 19808. In addition, all patients on CALGB 9621 who achieved CR were assigned to receive interleukin-2, whereas on CALGB 19808, patients were randomly assigned to either receive interleukin-2 or observation.

Criteria for Response, Relapse, and Definition of Clinical End Points

CR was defined by bone marrow (BM) cellularity of at least 20%, lower than 5% leukemic blasts, no Auer rods, and maturation in all cell lineages and blood recovery of leukocyte (≥ 1,500/μL) and platelet (> 100,000/μL) counts. Relapse was defined as reoccurrence of ≥ 5% of leukemic blasts in BM, reappearance of circulating blasts, or the development of extramedullary leukemia. Disease-free survival was defined as the interval from the date of CR until removal from study due to relapse or death from any cause, censoring for patients alive at last follow-up. Overall survival was defined as the date on study until death, censoring for patients alive at last follow-up.

Clinical Outcome

The CR rate for the 119 cases analyzed for the meningioma 1 (MN1) gene expression was not different from those 121 that were not analyzed (83% v 84%; P = .86). Likewise, the time to event end points were similar between the two groups (3 year DFS: 47% v 46%; P = .37; 3 years OS: 54% v 49%; P = .33).

MN1 Analysis

Mononuclear cells from pretreatment BM were enriched by Ficoll-Hypaque gradient and cryopreserved in liquid nitrogen until they were thawed at 37°C for this analysis. Total RNA extraction was performed using Trizol reagent (Invitrogen, Carlsbad, CA), and cDNA was synthesized using MMLV reverse transcriptase (Invitrogen) and random hexamers. Quantitative real-time RT-PCR assays were carried out in a final reaction volume of 10 μL using 1 μL of cDNA, 1x universal master mix (Applied Biosystems, Foster City, CA) and 250 nmol MN1 probe (5′-FAM AACAGCAAAGAAGCCCACGACCTCC-TAMRA) with 900 nmol MN1 forward (5′-GAAGGCCAAACCCCAGAAC) and reverse (5′-GATGCTGAGGCCTTGTTTGC) primers. Primers and probe were designed using Primer Express software v2.0 (Applied Biosystems). For ABL, used here as an internal control, the previously described primers and probes were used (Beillard E, Pallisgaard N, van der Velden VHJ, et al: Leukemia 17:2474-2486, 2003). Samples were tested in duplicates on the 7900HT Fast Real-Time PCR System (Applied Biosystems). Positive controls (cDNA from the MN1 expressing cell line KG1a), negative controls (water control of the cDNA synthesis), and standard curves (serial dilutions of plasmids containing MN1 or ABL cloned fragments) were included in each run. MN1 copy numbers were measured and normalized to the copy numbers of ABL using standard curves constructed as reported previously (Marcucci G, Caligiuri MA, Döhner H, et al: Leukemia 15:1072-1080, 2001).

The independent prognostic value of MN1 expression was evaluated in the context of other prognostic clinical and molecular markers, as detailed in the statistical section of the article. For the statistical analyses, we did not impute missing data. Patients with available data on all variables were used in each step of the multivariable analyses.

Microarray Data Analysis

RNA samples from patients enrolled on CALGB 19808 and studied for MN1 expression were analyzed for genome-wide gene expression using Affymetrix U133 plus 2.0 GeneChips (Affymetrix). Double-stranded cDNA was prepared (Invitrogen, Carlsbad, CA) from total RNA using T7-Oligo(dT) primer (Affymetrix). In vitro transcription was performed with the BioArray HighYield RNA Transcript Labeling Kit (T7) (Enzo Life Science, Farmingdale, NY). Fragmented, biotinylated RNA samples were hybridized to the U133 plus 2.0 GeneChip for 16 hours at 45°C. Scanned images were converted to CEL files using GCOS software (Affymetrix).

For the gene expression microarrays, summary measures of the expression levels were computed for each probe set using the robust multichip average method, which incorporates quantile normalization of arrays (Irizarry RA, Bolstad BM, Collin F, et al: Nucleic Acids Res 31:e15, 2003). Expression values were logged (base 2) before analysis. A filtering step was performed to remove probe sets that did not display significant variation in expression across arrays. In this procedure, a χ2 test was used to test whether the observed variance in expression of a probe set was significantly larger than the median observed variance in expression for all probe sets using α = .01 as the significance level. A total of 24,183 probe sets passed the filtering criterion and were included in subsequent analyses.

RNA samples from patients enrolled on CALGB 19808 and studied for MN1 expression were also analyzed for genome-wide microRNA expression with microRNA microarray chips as previously reported (Marcucci G, Radmacher MD, Maharry K, et al: N Engl J Med 358:1919-1928, 2008). For microRNA microarrays, the signal intensity was calculated for each spot without adjusting for local background. Spots with a low signal-to-noise ratio were considered as missing values. Intensities were log-transformed and log-intensities from replicate spots were averaged. A median-centering normalization was performed based on all human microRNA probes represented on the array. MicroRNA probes with a low signal-to-noise ratio on 50% or more of arrays were excluded from subsequent analyses, reducing the number of examined human microRNA probes in the training set to 305. For each microRNA probe, an adjustment was made for batch effects (ie, differences in expression related to the batch in which arrays were hybridized). The batch adjustment was made by fitting a linear model for the expression values of each microRNA probe with array batch as the factor. A correction to the expression values was then made for the measured batch effects.

Microarray expression analyses were performed using BRB-ArrayTools version 3.7.0 (R. Simon, A.P. Lam, National Cancer Institute, Bethesda, MD) and using the R version 2.5.1 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org/).

Gene Ontology Analysis

We tested separately which gene ontology terms for biologic processes were over-represented among the genes that positively and negatively correlated with MN1 expression levels. An over-represented term is one for which more members assigned to that term are found in the microarray signature than would be expected by chance. In our analysis, we only considered gene ontology terms for biologic processes for which at least 5 members (ie, genes) of the term were included in our microarray analysis. GenMAPP version 2.1 and MAPPFinder version 2.1 (Dahlquist KD, Salomonis N, Vranizan K, et al: Nat Genet 31:19-20, 2002) were used to assess over-represented gene ontologies among the genes comprising the identified signature. MAPPFinder uses a permutation procedure to determine the over-represented gene ontologies; a permutation P value of < .005 was considered significant.

Table A1.

Signature of 555 Affymetrix Probe Sets Significantly Correlated With MN1 Expression Level, Grouped by Direction of Correlation and Ordered Alphabetically by Gene Symbol

Probe Set Gene Symbol Name Pearson Correlation P
Positively correlated with MN1 expression
    209993_at ABCB1 ATP-binding cassette, sub-family B (MDR/TAP), member 1 0.468 2.29E-05
    209994_s_at ABCB1 ATP-binding cassette, sub-family B (MDR/TAP), member 1 0.458 3.66E-05
    243951_at ABCB1 ATP-binding cassette, sub-family B (MDR/TAP), member 1 0.446 6.14E-05
    202850_at ABCD3 ATP-binding cassette, sub-family D (ALD), member 3 0.373 .000987
    232081_at ABCG1 ATP-binding cassette, sub-family G (WHITE), member 1 0.491 7.70E-06
    204567_s_at ABCG1 ATP-binding cassette, sub-family G (WHITE), member 1 0.381 .000755
    1570432_at ABCG1 ATP-binding cassette, sub-family G (WHITE), member 1 0.373 .000968
    204638_at ACP5 Acid phosphatase 5, tartrate resistant 0.453 4.49E-05
    1554974_at ACY3 Aspartoacylase (aminocyclase) 3 0.412 .00024
    230481_at ACY3 Aspartoacylase (aminocyclase) 3 0.375 .000912
    209321_s_at ADCY3 Adenylate cyclase 3 0.463 2.84E-05
    209320_at ADCY3 Adenylate cyclase 3 0.378 .000833
    221718_s_at AKAP13 A kinase (PRKA) anchor protein 13 0.432 .000108
    224884_at AKAP13 A kinase (PRKA) anchor protein 13 0.388 .000585
    208325_s_at AKAP13 A kinase (PRKA) anchor protein 13 0.380 .000786
    200602_at APP Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) 0.410 .000258
    237571_at APP Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) 0.385 .000639
    239567_at ARHGAP10 Rho GTPase activating protein 10 0.450 5.13E-05
    225166_at ARHGAP18 Rho GTPase activating protein 18 0.470 2.09E-05
    222780_s_at BAALC Brain and acute leukemia, cytoplasmic 0.569 1E-07
    218899_s_at BAALC Brain and acute leukemia, cytoplasmic 0.561 2E-07
    210201_x_at BIN1 Bridging integrator 1 0.382 .00073
    214439_x_at BIN1 Bridging integrator 1 0.379 .000801
    229801_at C10orf47 Chromosome 10 open reading frame 47 0.439 8.08E-05
    230051_at C10orf47 Chromosome 10 open reading frame 47 0.416 .000207
    233138_at C18orf1 Chromosome 18 open reading frame 1 0.439 8.10E-05
    242551_at C18orf1 Chromosome 18 open reading frame 1 0.438 8.64E-05
    210785_s_at C1orf38 Chromosome 1 open reading frame 38 0.455 4.10E-05
    207571_x_at C1orf38 Chromosome 1 open reading frame 38 0.451 4.83E-05
    223039_at C22orf13 Chromosome 22 open reading frame 13 0.418 .000187
    221823_at C5orf30 Chromosome 5 open reading frame 30 0.378 .000814
    1554486_a_at C6orf114 Chromosome 6 open reading frame 114 0.378 .000839
    223075_s_at C9orf58 Chromosome 9 open reading frame 58 0.403 .000337
    209583_s_at CD200 CD200 molecule 0.514 2.40E-06
    209582_s_at CD200 CD200 molecule 0.470 2.08E-05
    203593_at CD2AP CD2-associated protein 0.466 2.55E-05
    209933_s_at CD300A CD300a molecule 0.442 7.18E-05
    217078_s_at CD300A CD300a molecule 0.392 .000511
    209543_s_at CD34 CD34 molecule 0.431 .000114
    209619_at CD74 CD74 molecule, major histocompatibility complex, class II invariant chain 0.389 .00057
    218451_at CDCP1 CUB domain containing protein 1 0.387 .000611
    239317_at CEACAM21 Carcinoembryonic antigen-related cell adhesion molecule 21 0.563 1E-07
    213618_at CENTD1 Centaurin, delta 1 0.444 6.55E-05
    206210_s_at CETP Cholesteryl ester transfer protein, plasma 0.436 9.35E-05
    219161_s_at CKLF Chemokine-like factor 0.483 1.15E-05
    221058_s_at CKLF Chemokine-like factor 0.433 .000104
    231219_at CKLF Chemokine-like factor 0.415 .000216
    1556209_at CLEC2B C-type lectin domain family 2, member B 0.544 4.00E-07
    209732_at CLEC2B C-type lectin domain family 2, member B 0.444 6.50E-05
    226425_at CLIP4 CAP-GLY domain containing linker protein family, member 4 0.399 .000399
    229967_at CMTM2 CKLF-like MARVEL transmembrane domain containing 2 0.387 .000608
    225009_at CMTM4 CKLF-like MARVEL transmembrane domain containing 4 0.415 .000212
    227953_at CMTM6 CKLF-like MARVEL transmembrane domain containing 6 0.417 .000199
    203642_s_at COBLL1 COBL-like 1 0.536 7.00E-07
    203641_s_at COBLL1 COBL-like 1 0.437 8.88E-05
    202119_s_at CPNE3 Copine III 0.422 .000163
    202118_s_at CPNE3 Copine III 0.400 .000381
    205984_at CRHBP Corticotropin releasing hormone binding protein 0.527 1.20E-06
    201380_at CRTAP Cartilage associated protein 0.391 .00053
    207532_at CRYGD Crystallin, gamma D 0.387 .000599
    207030_s_at CSRP2 Cysteine and glycine-rich protein 2 0.459 3.42E-05
    211126_s_at CSRP2 Cysteine and glycine-rich protein 2 0.442 7.08E-05
    215785_s_at CYFIP2 Cytoplasmic FMR1 interacting protein 2 0.385 .000642
    222134_at DDO D-aspartate oxidase 0.411 .000246
    1558742_at DEXI Dexamethasone-induced transcript 0.382 .000731
    202481_at DHRS3 Dehydrogenase/reductase (SDR family) member 3 0.429 .00012
    212888_at DICER1 Dicer1, Dcr-1 homolog (Drosophila) 0.373 .000995
    232252_at DUSP27 Dual specificity phosphatase 27 (putative) 0.379 .000802
    239574_at ECHDC3 Enoyl Coenzyme A hydratase domain containing 3 0.424 .000153
    218825_at EGFL7 EGF-like-domain, multiple 7 0.453 4.55E-05
    225159_s_at ELK4 ELK4, ETS-domain protein (SRF accessory protein 1) 0.376 .000881
    201325_s_at EMP1 Epithelial membrane protein 1 0.470 2.13E-05
    201324_at EMP1 Epithelial membrane protein 1 0.443 6.85E-05
    228256_s_at EPB41L4A Erythrocyte membrane protein band 4.1 like 4A 0.393 .000482
    202609_at EPS8 Epidermal growth factor receptor pathway substrate 8 0.381 .00076
    32259_at EZH1 Enhancer of zeste homolog 1 (Drosophila) 0.472 1.87E-05
    213506_at F2RL1 Coagulation factor II (thrombin) receptor-like 1 0.602 < 1e-07
    206429_at F2RL1 Coagulation factor II (thrombin) receptor-like 1 0.513 2.60E-06
    228678_at FAM116B Family with sequence similarity 116, member B 0.395 .000454
    217967_s_at FAM129A Family with sequence similarity 129, member A 0.497 5.80E-06
    217966_s_at FAM129A Family with sequence similarity 129, member A 0.484 1.08E-05
    208229_at FGFR2 Fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome) 0.411 .000246
    1562433_at FLJ10489 Hypothetical protein FLJ10489 0.582 < 1e-07
    1555486_a_at FLJ14213 Hypothetical protein FLJ14213 0.524 1.40E-06
    219383_at FLJ14213 Hypothetical protein FLJ14213 0.518 1.90E-06
    233379_at FLJ14213 Hypothetical protein FLJ14213 0.501 4.80E-06
    236322_at FLJ31951 Hypothetical protein FLJ31951 0.434 9.83E-05
    238949_at FLJ31951 Hypothetical protein FLJ31951 0.398 .000406
    226077_at FLJ31951 Hypothetical protein FLJ31951 0.379 .000788
    215330_at FLJ43663 Hypothetical protein FLJ43663 0.457 3.72E-05
    228702_at FLJ43663 Hypothetical protein FLJ43663 0.447 5.84E-05
    242768_at FLJ43663 Hypothetical protein FLJ43663 0.435 9.60E-05
    239901_at FLJ43663 Hypothetical protein FLJ43663 0.398 .000411
    238619_at FLJ43663 Hypothetical protein FLJ43663 0.385 .000647
    218084_x_at FXYD5 FXYD domain containing ion transport regulator 5 0.413 .000233
    224252_s_at FXYD5 FXYD domain containing ion transport regulator 5 0.412 .000238
    203987_at FZD6 Frizzled homolog 6 (Drosophila) 0.512 2.60E-06
    1557030_at GAB1 GRB2-associated binding protein 1 0.415 .000216
    227428_at GABPA GA binding protein transcription factor, alpha subunit 60kDa 0.397 .000422
    203765_at GCA Grancalcin, EF-hand calcium binding protein 0.422 .000164
    228376_at GGTA1 Glycoprotein, alpha-galactosyltransferase 1 0.405 .000309
    209276_s_at GLRX Glutaredoxin (thioltransferase) 0.407 .00029
    207987_s_at GNRH1 Gonadotropin-releasing hormone 1 (luteinizing-releasing hormone) 0.617 < 1e-07
    235540_at GNRH1 Gonadotropin-releasing hormone 1 (luteinizing-releasing hormone) 0.473 1.79E-05
    219313_at GRAMD1C GRAM domain containing 1C 0.381 .000759
    200696_s_at GSN Gelsolin (amyloidosis, Finnish type) 0.396 .000439
    1557915_s_at GSTO1 Glutathione S-transferase omega 1 0.453 4.43E-05
    201470_at GSTO1 Glutathione S-transferase omega 1 0.449 5.40E-05
    217436_x_at HLA-A Major histocompatibility complex, class I, A 0.437 8.74E-05
    211911_x_at HLA-B Major histocompatibility complex, class I, B 0.431 .000111
    209140_x_at HLA-B Major histocompatibility complex, class I, B 0.414 .000223
    208729_x_at HLA-B Major histocompatibility complex, class I, B 0.405 .000317
    208812_x_at HLA-C Major histocompatibility complex, class I, C 0.454 4.23E-05
    214459_x_at HLA-C Major histocompatibility complex, class I, C 0.426 .000137
    211799_x_at HLA-C Major histocompatibility complex, class I, C 0.403 .000342
    216526_x_at HLA-C Major histocompatibility complex, class I, C 0.400 .000384
    217478_s_at HLA-DMA Major histocompatibility complex, class II, DM alpha 0.452 4.77E-05
    226878_at HLA-DOA Major histocompatibility complex, class II, DO alpha 0.400 .000375
    211991_s_at HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 0.438 8.49E-05
    211990_at HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 0.426 .000139
    201137_s_at HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 0.480 1.29E-05
    244485_at HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 0.469 2.21E-05
    208894_at HLA-DRA Major histocompatibility complex, class II, DR alpha 0.425 .000145
    210982_s_at HLA-DRA Major histocompatibility complex, class II, DR alpha 0.411 .000245
    209312_x_at HLA-DRB1 Major histocompatibility complex, class II, DR beta 1 0.420 .000179
    215193_x_at HLA-DRB1 Major histocompatibility complex, class II, DR beta 1 0.415 .000212
    208306_x_at HLA-DRB4 Major histocompatibility complex, class II, DR beta 4 0.421 .000167
    204670_x_at HLA-DRB5 Major histocompatibility complex, class II, DR beta 5 0.431 .000114
    217362_x_at HLA-DRB6 Major histocompatibility complex, class II, DR beta 6 (pseudogene) 0.423 .000157
    200904_at HLA-E Major histocompatibility complex, class I, E 0.391 .000533
    217456_x_at HLA-E Major histocompatibility complex, class I, E 0.377 .000845
    204806_x_at HLA-F Major histocompatibility complex, class I, F 0.400 .000375
    221875_x_at HLA-F Major histocompatibility complex, class I, F 0.379 .000798
    211529_x_at HLA-G HLA-G histocompatibility antigen, class I, G 0.465 2.69E-05
    210514_x_at HLA-G HLA-G histocompatibility antigen, class I, G 0.462 3.03E-05
    211530_x_at HLA-G HLA-G histocompatibility antigen, class I, G 0.454 4.39E-05
    211528_x_at HLA-G HLA-G histocompatibility antigen, class I, G 0.434 9.96E-05
    211597_s_at HOP Homeodomain-only protein 0.375 .00093
    210253_at HTATIP2 HIV-1 Tat interactive protein 2, 30kDa 0.497 5.70E-06
    239704_at IBRDC2 IBR domain containing 2 0.497 5.60E-06
    228153_at IBRDC2 IBR domain containing 2 0.376 .000879
    208966_x_at IFI16 Interferon, gamma-inducible protein 16 0.438 8.43E-05
    208965_s_at IFI16 Interferon, gamma-inducible protein 16 0.432 .000107
    206332_s_at IFI16 Interferon, gamma-inducible protein 16 0.423 .000154
    204439_at IFI44L Interferon-induced protein 44-like 0.380 .000786
    226267_at JDP2 Jun dimerization protein 2 0.487 9.40E-06
    239835_at KBTBD8 Kelch repeat and BTB (POZ) domain containing 8 0.401 .000369
    224316_at KCTD9 Potassium channel tetramerisation domain containing 9 0.471 1.96E-05
    218823_s_at KCTD9 Potassium channel tetramerisation domain containing 9 0.436 9.22E-05
    229878_at KIAA1731 KIAA1731 0.427 .000133
    221221_s_at KLHL3 Kelch-like 3 (Drosophila) 0.437 8.77E-05
    200650_s_at LDHA Lactate dehydrogenase A 0.379 .000809
    212658_at LHFPL2 Lipoma HMGIC fusion partner-like 2 0.406 .000301
    219541_at LIME1 Lck interacting transmembrane adaptor 1 0.374 .000937
    223925_s_at LOC767558 Myeloproliferative disease-associated SEREX antigen 0.424 .000151
    210102_at LOH11CR2A Loss of heterozygosity, 11, chromosomal region 2, gene A 0.466 2.54E-05
    205011_at LOH11CR2A Loss of heterozygosity, 11, chromosomal region 2, gene A 0.461 3.15E-05
    240338_at LRAP Leukocyte-derived arginine aminopeptidase 0.383 .000694
    203523_at LSP1 Lymphocyte-specific protein 1 0.442 7.25E-05
    202145_at LY6E Lymphocyte antigen 6 complex, locus E 0.398 .000403
    224480_s_at MAG1 Lung cancer metastasis-associated protein 0.420 .000178
    1569136_at MGAT4A Mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetylglucosaminyltransferase, isozyme A 0.539 6.00E-07
    1558166_at MGC16275 Hypothetical protein MGC16275 0.406 .000297
    206247_at MICB MHC class I polypeptide-related sequence B 0.394 .000477
    239272_at MMP28 Matrix metallopeptidase 28 0.501 4.80E-06
    205330_at MN1 Meningioma (disrupted in balanced translocation) 1 0.866 < 1e-07
    219648_at MREG Melanoregulin 0.499 5.30E-06
    218027_at MRPL15 Mitochondrial ribosomal protein L15 0.374 .000931
    219363_s_at MTERFD1 MTERF domain containing 1 0.403 .000336
    225111_s_at NAPB N-ethylmaleimide-sensitive factor attachment protein, beta 0.399 .000395
    243246_at NAT12 N-acetyltransferase 12 0.422 .000161
    236197_at NCBP1 Nuclear cap binding protein subunit 1, 80kDa 0.491 7.70E-06
    240824_at OBFC1 Oligonucleotide/oligosaccharide-binding fold containing 1 0.493 7.10E-06
    223259_at ORMDL3 ORM1-like 3 (S. cerevisiae) 0.402 .000345
    228966_at PANK2 Pantothenate kinase 2 (Hallervorden-Spatz syndrome) 0.423 .000158
    232140_at PGM5P1 Phosphoglucomutase 5 pseudogene 1 0.393 .000494
    235389_at PHF20 PHD finger protein 20 0.393 .000486
    209780_at PHTF2 Putative homeodomain transcription factor 2 0.400 .000382
    206370_at PIK3CG Phosphoinositide-3-kinase, catalytic, gamma polypeptide 0.395 .000447
    235230_at PLCXD2 Phosphatidylinositol-specific phospholipase C, X domain containing 2 0.396 .000443
    201136_at PLP2 Proteolipid protein 2 (colonic epithelium-enriched) 0.384 .000684
    213241_at PLXNC1 Plexin C1 0.460 3.34E-05
    206470_at PLXNC1 Plexin C1 0.418 .000188
    206471_s_at PLXNC1 Plexin C1 0.414 .000223
    209799_at PRKAA1 Protein kinase, AMP-activated, alpha 1 catalytic subunit 0.426 .00014
    222582_at PRKAG2 Protein kinase, AMP-activated, gamma 2 non-catalytic subunit 0.389 .000555
    214203_s_at PRODH Proline dehydrogenase (oxidase) 1 0.422 .000163
    204304_s_at PROM1 Prominin 1 0.406 .000301
    241133_at PRSS1 Protease, serine, 1 (trypsin 1) 0.431 .000113
    240766_at PRSS1 Protease, serine, 1 (trypsin 1) 0.399 .000388
    209040_s_at PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 0.470 2.05E-05
    204279_at PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 0.406 .000298
    201087_at PXN Paxillin 0.446 6.01E-05
    230405_at RAD50 RAD50 homolog (S. cerevisiae) 0.467 2.42E-05
    232253_at RAD50 RAD50 homolog (S. cerevisiae) 0.415 .000211
    235846_at RAD54B RAD54 homolog B (S. cerevisiae) 0.413 .000234
    204070_at RARRES3 Retinoic acid receptor responder (tazarotene induced) 3 0.465 2.62E-05
    221827_at RBCK1 RanBP-type and C3HC4-type zinc finger containing 1 0.401 .000362
    218117_at RBX1 Ring-box 1 0.384 .000682
    227425_at REPS2 RALBP1 associated Eps domain containing 2 0.449 5.39E-05
    242571_at REPS2 RALBP1 associated Eps domain containing 2 0.430 .000117
    220570_at RETN Resistin 0.404 .000323
    214000_s_at RGS10 Regulator of G-protein signalling 10 0.425 .000144
    204319_s_at RGS10 Regulator of G-protein signalling 10 0.411 .000247
    219045_at RHOF ras homolog gene family, member F (in filopodia) 0.414 .000219
    243178_at RNF149 Ring finger protein 149 0.373 .000989
    229543_at RP1-93H18.5 Hypothetical protein LOC441168 0.561 2E-07
    228362_s_at RP1-93H18.5 Hypothetical protein LOC441168 0.543 5.00E-07
    229391_s_at RP1-93H18.5 Hypothetical protein LOC441168 0.525 1.30E-06
    229390_at RP1-93H18.5 Hypothetical protein LOC441168 0.524 1.40E-06
    226335_at RPS6KA3 Ribosomal protein S6 kinase, 90kDa, polypeptide 3 0.428 .000127
    1554876_a_at S100Z S100 calcium binding protein Z 0.472 1.89E-05
    226169_at SBF2 SET binding factor 2 0.470 2.08E-05
    242935_at SBF2 SET binding factor 2 0.440 7.88E-05
    233914_s_at SBF2 SET binding factor 2 0.421 .000171
    206995_x_at SCARF1 Scavenger receptor class F, member 1 0.374 .000935
    41220_at SEPT9 Septin 9 0.382 .000723
    211474_s_at SERPINB6 Serpin peptidase inhibitor, clade B (ovalbumin), member 6 0.458 3.54E-05
    1556950_s_at SERPINB6 Serpin peptidase inhibitor, clade B (ovalbumin), member 6 0.416 .000202
    209723_at SERPINB9 Serpin peptidase inhibitor, clade B (ovalbumin), member 9 0.453 4.53E-05
    242814_at SERPINB9 Serpin peptidase inhibitor, clade B (ovalbumin), member 9 0.402 .000354
    218346_s_at SESN1 Sestrin 1 0.384 .000662
    241245_at SFRS4 Splicing factor, arginine/serine-rich 4 0.406 .000297
    201811_x_at SH3BP5 SH3-domain binding protein 5 (BTK-associated) 0.377 .000868
    219256_s_at SH3TC1 SH3 domain and tetratricopeptide repeats 1 0.386 .000622
    203124_s_at SLC11A2 Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 0.374 .000951
    226601_at SLC30A7 Solute carrier family 30 (zinc transporter), member 7 0.377 .000859
    212944_at SLC5A3 Solute carrier family 5 (inositol transporters), member 3 0.405 .00031
    206543_at SMARCA2 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 0.388 .000586
    219109_at SPAG16 Sperm associated antigen 16 0.440 7.87E-05
    212667_at SPARC Secreted protein, acidic, cysteine-rich (osteonectin) 0.476 1.57E-05
    200665_s_at SPARC Secreted protein, acidic, cysteine-rich (osteonectin) 0.460 3.30E-05
    213820_s_at STARD5 START domain containing 5 0.404 .000323
    201061_s_at STOM Stomatin 0.461 3.23E-05
    201060_x_at STOM Stomatin 0.393 .000489
    226117_at TIFA TRAF-interacting protein with a forkhead-associated domain 0.431 .000112
    241844_x_at TMEM156 Transmembrane protein 156 0.376 .000893
    231775_at TNFRSF10A Tumor necrosis factor receptor superfamily, member 10a 0.426 .00014
    209354_at TNFRSF14 Tumor necrosis factor receptor superfamily, member 14 (herpesvirus entry mediator) 0.373 .000972
    214581_x_at TNFRSF21 Tumor necrosis factor receptor superfamily, member 21 0.413 .00023
    218856_at TNFRSF21 Tumor necrosis factor receptor superfamily, member 21 0.403 .000335
    235973_at TRIP11 Thyroid hormone receptor interactor 11 0.431 .000114
    225775_at TSPAN33 Tetraspanin 33 0.515 2.30E-06
    213172_at TTC9 Tetratricopeptide repeat domain 9 0.388 .00059
    1553183_at UMODL1 Uromodulin-like 1 0.444 6.73E-05
    208844_at VDAC3 Voltage-dependent anion channel 3 0.394 .000477
    205672_at XPA Xeroderma pigmentosum, complementation group A 0.456 3.93E-05
    230913_at 0.496 5.90E-06
    226550_at 0.482 1.19E-05
    239184_at 0.478 1.44E-05
    240153_at 0.477 1.49E-05
    1558105_a_at 0.452 4.74E-05
    231431_s_at 0.446 5.99E-05
    237315_at 0.435 9.54E-05
    210824_at 0.422 .000159
    233867_at 0.415 .000213
    229380_at 0.393 .000481
    232227_at 0.387 .000606
    229011_at 0.385 .00064
    225567_at 0.382 .000726
    244561_at 0.380 .000766
Negatively correlated with MN1 expression
    218434_s_at AACS Acetoacetyl-CoA synthetase −0.427 1.32E-04
    1553605_a_at ABCA13 ATP-binding cassette, sub-family A (ABC1), member 13 −0.393 .000485
    210377_at ACSM3 Acyl-CoA synthetase medium-chain family member 3 −0.413 2.34E-04
    205942_s_at ACSM3 Acyl-CoA synthetase medium-chain family member 3 −0.417 2.00E-04
    201792_at AEBP1 AE binding protein 1 −0.437 8.81E-05
    212173_at AK2 Adenylate kinase 2 −0.486 9.9E-06
    212747_at ANKS1A Ankyrin repeat and sterile alpha motif domain containing 1A −0.533 9E-07
    225286_at ARSD Arylsulfatase D −0.374 .000955
    223695_s_at ARSD Arylsulfatase D −0.375 .000918
    230131_x_at ARSD Arylsulfatase D −0.384 .000673
    204608_at ASL Argininosuccinate lyase −0.381 .00075
    218908_at ASPSCR1 Alveolar soft part sarcoma chromosome region, candidate 1 −0.395 .000461
    240747_at ATP8B4 ATPase, Class I, type 8B, member 4 −0.377 .00086
    220416_at ATP8B4 ATPase, Class I, type 8B, member 4 −0.423 1.55E-04
    227877_at AXIIR Similar to annexin II receptor −0.416 2.06E-04
    203304_at BAMBI BMP and activin membrane-bound inhibitor homolog (Xenopus laevis) −0.509 .000003
    218332_at BEX1 Brain expressed, X-linked 1 −0.428 1.27E-04
    202265_at BMI1 BMI1 polycomb ring finger oncogene −0.388 .000588
    213578_at BMPR1A Bone morphogenetic protein receptor, type IA −0.412 2.38E-04
    240772_at C10orf11 Chromosome 10 open reading frame 11 −0.487 9.4E-06
    223703_at C10orf11 Chromosome 10 open reading frame 11 −0.511 2.8E-06
    219988_s_at C1orf164 Chromosome 1 open reading frame 164 −0.404 .000322
    230381_at C1orf186 Chromosome 1 open reading frame 186 −0.394 .000473
    223063_at C1orf198 Chromosome 1 open reading frame 198 −0.373 .000974
    219951_s_at C20orf12 Chromosome 20 open reading frame 12 −0.388 .000579
    238767_at C4orf36 Chromosome 4 open reading frame 36 −0.394 .000476
    201309_x_at C5orf13 Chromosome 5 open reading frame 13 −0.396 .000442
    201310_s_at C5orf13 Chromosome 5 open reading frame 13 −0.410 2.62E-04
    238465_at C5orf35 Chromosome 5 open reading frame 35 −0.430 1.19E-04
    219261_at C7orf26 Chromosome 7 open reading frame 26 −0.379 .000811
    232668_at C8orf72 Chromosome 8 open reading frame 72 −0.462 3.07E-05
    228790_at C8orf72 Chromosome 8 open reading frame 72 −0.482 .000012
    221959_at C8orf72 Chromosome 8 open reading frame 72 −0.498 5.5E-06
    207129_at CA5B Carbonic anhydrase VB, mitochondrial −0.397 .000418
    214082_at CA5B Carbonic anhydrase VB, mitochondrial −0.413 2.33E-04
    243416_at CACHD1 Cache domain containing 1 −0.445 6.40E-05
    225627_s_at CACHD1 Cache domain containing 1 −0.464 2.77E-05
    210817_s_at CALCOCO2 Calcium binding and coiled-coil domain 2 −0.374 .000958
    220162_s_at CARD9 Caspase recruitment domain family, member 9 −0.411 2.52E-04
    201432_at CAT Catalase −0.495 6.3E-06
    211922_s_at CAT Catalase −0.510 .000003
    228061_at CCDC126 Coiled-coil domain containing 126 −0.379 .000792
    237305_at CDH2 Cadherin 2, type 1, N-cadherin (neuronal) −0.403 .000338
    222755_s_at CHD7 Chromodomain helicase DNA binding protein 7 −0.504 .000004
    226123_at CHD7 Chromodomain helicase DNA binding protein 7 −0.509 3.1E-06
    218829_s_at CHD7 Chromodomain helicase DNA binding protein 7 −0.511 2.9E-06
    205131_x_at CLEC11A C-type lectin domain family 11, member A −0.388 .000587
    210783_x_at CLEC11A C-type lectin domain family 11, member A −0.403 .000336
    227209_at CNTN1 Contactin 1 −0.398 .000402
    212489_at COL5A1 Collagen, type V, alpha 1 −0.377 .000857
    212488_at COL5A1 Collagen, type V, alpha 1 −0.419 1.83E-04
    213622_at COL9A2 Collagen, type IX, alpha 2 −0.446 5.96E-05
    223457_at COPG2 Coatomer protein complex, subunit gamma 2 −0.400 .000384
    205624_at CPA3 Carboxypeptidase A3 (mast cell) −0.453 4.49E-05
    205653_at CTSG Cathepsin G −0.385 .000642
    229415_at CYCS Cytochrome c, somatic −0.388 .000584
    1567101_at DACH1 Dachshund homolog 1 (Drosophila) −0.374 .000934
    217025_s_at DBN1 Drebrin 1 −0.376 .000893
    210397_at DEFB1 Defensin, beta 1 −0.398 .000414
    207147_at DLX2 Distal-less homeobox 2 −0.384 .000674
    228598_at DPP10 Dipeptidyl-peptidase 10 −0.373 .000985
    238784_at DPY19L2 dpy-19-like 2 (C. elegans) −0.393 .000491
    204750_s_at DSC2 Desmocollin 2 −0.424 1.52E-04
    204751_x_at DSC2 Desmocollin 2 −0.445 6.28E-05
    226817_at DSC2 Desmocollin 2 −0.462 3.03E-05
    205741_s_at DTNA Dystrobrevin, alpha −0.467 2.38E-05
    210091_s_at DTNA Dystrobrevin, alpha −0.477 1.49E-05
    227084_at DTNA Dystrobrevin, alpha −0.481 1.24E-05
    1557803_at DTNA Dystrobrevin, alpha −0.536 7E-07
    219469_at DYNC2H1 Dynein, cytoplasmic 2, heavy chain 1 −0.383 .000688
    1565149_at DYNC2H1 Dynein, cytoplasmic 2, heavy chain 1 −0.410 2.55E-04
    205107_s_at EFNA4 Ephrin-A4 −0.399 .000397
    1558871_at EPGN Epithelial mitogen homolog (mouse) −0.522 1.5E-06
    203349_s_at ETV5 ets variant gene 5 (ets-related molecule) −0.389 .000553
    201828_x_at FAM127A Family with sequence similarity 127, member A −0.396 .000444
    224973_at FAM46A Family with sequence similarity 46, member A −0.383 .000685
    221766_s_at FAM46A Family with sequence similarity 46, member A −0.423 1.53E-04
    229546_at FAM84A Family with sequence similarity 84, member A −0.398 .000412
    228459_at FAM84A Family with sequence similarity 84, member A −0.399 .000395
    234331_s_at FAM84A Family with sequence similarity 84, member A −0.469 2.24E-05
    225667_s_at FAM84A Family with sequence similarity 84, member A −0.479 1.38E-05
    233087_at FBXL17 F-box and leucine-rich repeat protein 17 −0.402 .000348
    227203_at FBXL17 F-box and leucine-rich repeat protein 17 −0.424 1.50E-04
    238174_at FBXL17 F-box and leucine-rich repeat protein 17 −0.466 2.49E-05
    242034_at FBXL17 F-box and leucine-rich repeat protein 17 −0.477 .000015
    215000_s_at FEZ2 Fasciculation and elongation protein zeta 2 (zygin II) −0.406 .000301
    229280_s_at FLJ22536 Hypothetical locus LOC401237 −0.409 .000271
    212288_at FNBP1 Formin binding protein 1 −0.374 .000961
    209702_at FTO Fatso −0.511 2.8E-06
    204452_s_at FZD1 Frizzled homolog 1 (Drosophila) −0.383 .000689
    214106_s_at GMDS GDP-mannose 4,6-dehydratase −0.407 .000294
    204983_s_at GPC4 Glypican 4 −0.422 1.64E-04
    232453_at GPC6 Glypican 6 −0.387 .000613
    220773_s_at GPHN Gephyrin −0.384 .00068
    234941_s_at GPHN Gephyrin −0.417 1.96E-04
    221892_at H6PD Hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) −0.451 4.96E-05
    206643_at HAL Histidine ammonia-lyase −0.532 9E-07
    238021_s_at hCG_1815491 hCG1815491 −0.473 1.84E-05
    238022_at hCG_1815491 hCG1815491 −0.492 7.5E-06
    219687_at HHAT Hedgehog acyltransferase −0.377 .000855
    237466_s_at HHIP Hedgehog interacting protein −0.375 .000911
    1556037_s_at HHIP Hedgehog interacting protein −0.419 1.86E-04
    207982_at HIST1H1T Histone cluster 1, H1t −0.423 1.55E-04
    214522_x_at HIST1H2AD Histone cluster 1, H2ad −0.393 .000491
    239669_at HIST1H2AD Histone cluster 1, H2ad −0.529 1.1E-06
    214644_at HIST1H2AK Histone cluster 1, H2ak −0.394 .000464
    239041_at HIST1H2AK Histone cluster 1, H2ak −0.435 9.54E-05
    214455_at HIST1H2BC Histone cluster 1, H2bc −0.439 8.06E-05
    209911_x_at HIST1H2BD Histone cluster 1, H2bd −0.378 .000836
    222067_x_at HIST1H2BD Histone cluster 1, H2bd −0.380 .000781
    208527_x_at HIST1H2BE Histone cluster 1, H2be −0.403 .000341
    208490_x_at HIST1H2BF Histone cluster 1, H2bf −0.385 .000659
    236193_at HIST1H2BG Histone cluster 1, H2bg −0.464 2.73E-05
    208523_x_at HIST1H2BI Histone cluster 1, H2bi −0.404 .000331
    214502_at HIST1H2BJ Histone cluster 1, H2bj −0.383 .000704
    207226_at HIST1H2BN Histone cluster 1, H2bn −0.458 3.65E-05
    214472_at HIST1H3D Histone cluster 1, H3d −0.433 1.04E-04
    208076_at HIST1H4D Histone cluster 1, H4d −0.449 5.29E-05
    202708_s_at HIST2H2BE Histone cluster 2, H2be −0.446 6.08E-05
    1554453_at HNRPLL Heterogeneous nuclear ribonucleoprotein L-like −0.380 .000772
    225385_s_at HNRPLL Heterogeneous nuclear ribonucleoprotein L-like −0.456 3.88E-05
    204647_at HOMER3 Homer homolog 3 (Drosophila) −0.443 6.76E-05
    215489_x_at HOMER3 Homer homolog 3 (Drosophila) −0.476 1.62E-05
    222222_s_at HOMER3 Homer homolog 3 (Drosophila) −0.484 .000011
    214457_at HOXA2 Homeobox A2 −0.495 6.4E-06
    208604_s_at HOXA3 Homeobox A3 −0.394 .000476
    206289_at HOXA4 Homeobox A4 −0.382 .000717
    213844_at HOXA5 Homeobox A5 −0.374 .000956
    235521_at HOXA5 Homeobox A5 −0.400 .000373
    223963_s_at IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 −0.379 .000814
    218847_at IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 −0.383 .000695
    203006_at INPP5A Inositol polyphosphate-5-phosphatase, 40kDa −0.406 .000298
    203331_s_at INPP5D Inositol polyphosphate-5-phosphatase, 145kDa −0.374 .000946
    213392_at IQCK IQ motif containing K −0.386 .000622
    224572_s_at IRF2BP2 Interferon regulatory factor 2 binding protein 2 −0.464 2.77E-05
    224570_s_at IRF2BP2 Interferon regulatory factor 2 binding protein 2 −0.465 2.67E-05
    229638_at IRX3 Iroquois homeobox protein 3 −0.463 2.83E-05
    210239_at IRX5 Iroquois homeobox protein 5 −0.531 .000001
    226246_at KCTD1 Potassium channel tetramerisation domain containing 1 −0.384 .000665
    226245_at KCTD1 Potassium channel tetramerisation domain containing 1 −0.395 .000453
    228683_s_at KCTD15 Potassium channel tetramerisation domain containing 15 −0.397 .000426
    230249_at KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 −0.489 8.4E-06
    209781_s_at KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 −0.528 1.1E-06
    1556425_a_at KIAA0802 KIAA0802 −0.416 2.04E-04
    239033_at KIAA1958 KIAA1958 −0.405 .000315
    235112_at KIAA1958 KIAA1958 −0.432 1.09E-04
    213623_at KIF3A Kinesin family member 3A −0.390 .000546
    236565_s_at LARP6 La ribonucleoprotein domain family, member 6 −0.384 .000683
    207348_s_at LIG3 Ligase III, DNA, ATP-dependent −0.426 1.36E-04
    204123_at LIG3 Ligase III, DNA, ATP-dependent −0.483 1.12E-05
    240027_at LIN7A Lin-7 homolog A (C. elegans) −0.434 1.01E-04
    206440_at LIN7A Lin-7 homolog A (C. elegans) −0.488 8.9E-06
    241652_x_at LIN7A Lin-7 homolog A (C. elegans) −0.511 2.8E-06
    233336_at LOC142893 Hypothetical protein LOC142893 −0.411 2.52E-04
    230648_at LOC283663 Hypothetical protein LOC283663 −0.395 .000461
    241370_at LOC286052 Hypothetical protein LOC286052 −0.375 .000916
    227547_at LOC388795 Similar to CG40449-PA.3 −0.451 4.98E-05
    232113_at LOC399959 Hypothetical gene supported by BX647608 −0.404 .000331
    240423_at LOC441204 Hypothetical locus LOC441204 −0.444 6.75E-05
    229429_x_at LOC728855 Hypothetical protein LOC728855 −0.373 .000985
    202728_s_at LTBP1 Latent transforming growth factor beta binding protein 1 −0.497 5.8E-06
    202729_s_at LTBP1 Latent transforming growth factor beta binding protein 1 −0.518 .000002
    228150_at LZTR2 Leucine zipper transcription regulator 2 −0.399 .000388
    241607_at LZTR2 Leucine zipper transcription regulator 2 −0.430 1.16E-04
    1564423_a_at LZTR2 Leucine zipper transcription regulator 2 −0.450 5.09E-05
    242172_at MEIS1 Meis homeobox 1 −0.431 1.12E-04
    1559477_s_at MEIS1 Meis homeobox 1 −0.442 7.12E-05
    204069_at MEIS1 Meis homeobox 1 −0.462 3.01E-05
    238347_at MGC15523 Hypothetical protein MGC15523 −0.376 .000902
    242942_at MGC15523 Hypothetical protein MGC15523 −0.390 .000551
    210254_at MS4A3 Membrane-spanning 4-domains, subfamily A, member 3 (hematopoietic cell-specific) −0.475 1.66E-05
    1554892_a_at MS4A3 Membrane-spanning 4-domains, subfamily A, member 3 (hematopoietic cell-specific) −0.476 1.58E-05
    202247_s_at MTA1 Metastasis associated 1 −0.379 .000803
    204798_at MYB v-myb myeloblastosis viral oncogene homolog (avian) −0.434 9.98E-05
    209550_at NDN Necdin homolog (mouse) −0.391 .000532
    1552736_a_at NETO1 Neuropilin (NRP) and tolloid (TLL)-like 1 −0.416 2.03E-04
    209706_at NKX3-1 NK3 transcription factor related, locus 1 (Drosophila) −0.477 .000015
    232478_at NR6A1 Nuclear receptor subfamily 6, group A, member 1 −0.502 4.4E-06
    220110_s_at NXF3 Nuclear RNA export factor 3 −0.504 4.1E-06
    227492_at OCLN Occluding −0.407 .000287
    209925_at OCLN Occluding −0.455 4.05E-05
    223464_at OSBPL5 Oxysterol binding protein-like 5 −0.449 5.38E-05
    204082_at PBX3 Pre-B-cell leukemia homeobox 3 −0.391 .000526
    209361_s_at PCBP4 Poly(rC) binding protein 4 −0.392 .000515
    219737_s_at PCDH9 Protocadherin 9 −0.375 .000907
    222860_s_at PDGFD Platelet derived growth factor D −0.427 1.35E-04
    219304_s_at PDGFD Platelet derived growth factor D −0.490 .000008
    225829_at PDZD8 PDZ domain containing 8 −0.382 .000709
    225830_at PDZD8 PDZ domain containing 8 −0.402 .000347
    209438_at PHKA2 Phosphorylase kinase, alpha 2 (liver) −0.463 2.94E-05
    1559705_s_at PHKA2 Phosphorylase kinase, alpha 2 (liver) −0.489 8.5E-06
    209439_s_at PHKA2 Phosphorylase kinase, alpha 2 (liver) −0.521 1.6E-06
    225903_at PIGU Phosphatidylinositol glycan anchor biosynthesis, class U −0.389 .000568
    215807_s_at PLXNB1 Plexin B1 −0.428 1.28E-04
    228383_at PNPLA7 Patatin-like phospholipase domain containing 7 −0.477 1.49E-05
    222238_s_at POLM Polymerase (DNA directed), mu −0.395 .000448
    204117_at PREP Prolyl endopeptidase −0.426 1.37E-04
    37950_at PREP Prolyl endopeptidase −0.464 2.74E-05
    220798_x_at PRG2 Plasticity-related gene 2 −0.633 < 1e-07
    209158_s_at PSCD2 Pleckstrin homology, Sec7 and coiled-coil domains 2 (cytohesin-2) −0.414 2.24E-04
    211373_s_at PSEN2 Presenilin 2 (Alzheimer disease 4) −0.478 1.43E-05
    213933_at PTGER3 Prostaglandin E receptor 3 (subtype EP3) −0.430 1.19E-04
    1569830_at PTPRC Protein tyrosine phosphatase, receptor type, C −0.391 .000523
    1558290_a_at PVT1 Pvt1 oncogene homolog, MYC activator (mouse) −0.433 1.03E-04
    212013_at PXDN Peroxidasin homolog (Drosophila) −0.394 .000471
    201481_s_at PYGB Phosphorylase, glycogen; brain −0.449 5.30E-05
    222810_s_at RASAL2 RAS protein activator like 2 −0.581 < 1e-07
    244526_at RASGRP3 RAS guanyl releasing protein 3 (calcium and DAG-regulated) −0.423 1.59E-04
    205801_s_at RASGRP3 RAS guanyl releasing protein 3 (calcium and DAG-regulated) −0.454 4.22E-05
    208031_s_at RFX2 Regulatory factor X, 2 (influences HLA class II expression) −0.449 5.35E-05
    226872_at RFX2 Regulatory factor X, 2 (influences HLA class II expression) −0.458 3.53E-05
    91816_f_at RKHD1 Ring finger and KH domain containing 1 −0.384 .000676
    206851_at RNASE3 Ribonuclease, RNase A family, 3 (eosinophil cationic protein) −0.375 .00093
    1556590_s_at SAPS3 SAPS domain family, member 3 −0.418 1.93E-04
    1556589_at SAPS3 SAPS domain family, member 3 −0.426 1.38E-04
    228497_at SLC22A15 Solute carrier family 22 (organic cation transporter), member 15 −0.451 4.85E-05
    1563453_at SLC24A3 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 −0.481 1.22E-05
    57588_at SLC24A3 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 −0.552 3E-07
    234199_at SLC24A3 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 −0.562 2E-07
    219090_at SLC24A3 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 −0.568 1E-07
    233773_at SLC24A3 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 −0.572 1E-07
    219932_at SLC27A6 Solute carrier family 27 (fatty acid transporter), member 6 −0.376 .0009
    244018_at SLC2A9 Solute carrier family 2 (facilitated glucose transporter), member 9 −0.472 1.89E-05
    1556551_s_at SLC39A6 Solute carrier family 39 (zinc transporter), member 6 −0.389 .00057
    1555460_a_at SLC39A6 Solute carrier family 39 (zinc transporter), member 6 −0.405 .000318
    202089_s_at SLC39A6 Solute carrier family 39 (zinc transporter), member 6 −0.412 2.40E-04
    237833_s_at SNCAIP Synuclein, alpha interacting protein (synphilin) −0.416 2.04E-04
    219511_s_at SNCAIP Synuclein, alpha interacting protein (synphilin) −0.429 1.25E-04
    243486_at SND1 Staphylococcal nuclease and tudor domain containing 1 −0.380 .000786
    242736_at SORBS1 Sorbin and SH3 domain containing 1 −0.394 .000475
    213668_s_at SOX4 SRY (sex determining region Y)-box 4 −0.385 .000653
    201418_s_at SOX4 SRY (sex determining region Y)-box 4 −0.409 2.67E-04
    242086_at SPATA6 Spermatogenesis associated 6 −0.396 .00044
    1563595_at SRGAP3 SLIT-ROBO Rho GTPase activating protein 3 −0.412 2.43E-04
    215550_at SRGAP3 SLIT-ROBO Rho GTPase activating protein 3 −0.429 1.21E-04
    209794_at SRGAP3 SLIT-ROBO Rho GTPase activating protein 3 −0.467 2.42E-05
    204548_at STAR Steroidogenic acute regulator −0.494 6.6E-06
    208425_s_at TANC2 Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 −0.459 3.52E-05
    224952_at TANC2 Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 −0.459 3.48E-05
    205513_at TCN1 Transcobalamin I (vitamin B12 binding protein, R binder family) −0.467 2.39E-05
    209215_at TETRAN Tetracycline transporter-like protein −0.487 9.6E-06
    226050_at TMCO3 Transmembrane and coiled-coil domains 3 −0.395 .00046
    224916_at TMEM173 Transmembrane protein 173 −0.376 .000895
    241342_at TMEM65 Transmembrane protein 65 −0.403 .000334
    238045_at TMEM65 Transmembrane protein 65 −0.465 2.62E-05
    225802_at TOP1MT Topoisomerase (DNA) I, mitochondrial −0.424 1.49E-04
    224836_at TP53INP2 Tumor protein p53 inducible nuclear protein 2 −0.480 1.31E-05
    210882_s_at TRO Trophinin −0.389 .000558
    235737_at TSLP Thymic stromal lymphopoietin −0.401 .00037
    230625_s_at TSPAN12 Tetraspanin 12 −0.414 2.19E-04
    230626_at TSPAN12 Tetraspanin 12 −0.422 1.60E-04
    244248_at TTC27 Tetratricopeptide repeat domain 27 −0.457 3.79E-05
    218710_at TTC27 Tetratricopeptide repeat domain 27 −0.497 5.8E-06
    235749_at UGCGL2 UDP-glucose ceramide glucosyltransferase-like 2 −0.510 .000003
    1558466_at UGCGL2 UDP-glucose ceramide glucosyltransferase-like 2 −0.525 1.3E-06
    1555561_a_at UGCGL2 UDP-glucose ceramide glucosyltransferase-like 2 −0.565 1E-07
    1558467_a_at UGCGL2 UDP-glucose ceramide glucosyltransferase-like 2 −0.572 1E-07
    218801_at UGCGL2 UDP-glucose ceramide glucosyltransferase-like 2 −0.586 < 1e-07
    224048_at USP44 Ubiquitin specific peptidase 44 −0.499 5.2E-06
    201557_at VAMP2 Vesicle-associated membrane protein 2 (synaptobrevin 2) −0.373 .000995
    219330_at VANGL1 Vang-like 1 (van gogh, Drosophila) −0.378 .000838
    229997_at VANGL1 Vang-like 1 (van gogh, Drosophila) −0.382 .000727
    208626_s_at VAT1 Vesicle amine transport protein 1 homolog (T. californica) −0.541 6E-07
    239429_at ZNF323 Zinc finger protein 323 −0.426 1.41E-04
    240449_at ZNF341 Zinc finger protein 341 −0.387 .000599
    1561002_at ZNF521 Zinc finger protein 521 −0.439 8.01E-05
    230106_at ZXDC ZXD family zinc finger C −0.373 .000982
    218639_s_at ZXDC ZXD family zinc finger C −0.380 .000768
    228919_at −0.372 .000997
    240865_at −0.374 .000944
    230135_at −0.378 .000821
    232833_at −0.381 .000758
    235681_at −0.386 .000638
    235456_at −0.389 .000563
    243806_at −0.390 .000538
    228740_at −0.391 .000532
    243742_at −0.393 .00048
    1557443_s_at −0.394 .000473
    239488_at −0.399 .000385
    1556580_a_at −0.404 .000331
    240566_at −0.409 .000267
    243082_at −0.416 2.09E-04
    1555967_at −0.422 1.61E-04
    228349_at −0.425 1.44E-04
    1554599_x_at −0.426 1.38E-04
    236104_at −0.437 8.91E-05
    1554597_at −0.438 8.37E-05
    231233_at −0.449 5.36E-05
    220898_at −0.460 3.33E-05
    1559117_at −0.461 3.09E-05
    227929_at −0.479 .000014
    1555968_a_at −0.506 3.7E-06
    217521_at −0.515 2.3E-06
    227036_at −0.591 < 1e-07

Table A2.

GO Terms of Biological Processes Significantly Over-Represented in the Gene-Expression Signature Associated With MN1 Expression

GO ID GO Term Members of the GO Term Present in the Gene Expression Signature (%) P
GO terms over-represented among the genes positively correlated with MN1 expression
    2504 Antigen processing and presentation of peptide or polysaccharide antigen via MHC class II 47.06 < .001
    2478 Antigen processing and presentation of exogenous peptide antigen 42.86 .002
    2495 Antigen processing and presentation of peptide antigen via MHC class II 42.86 .002
    19,886 Antigen processing and presentation of exogenous peptide antigen via MHC class II 42.86 .002
    7618 Mating 40.00 .005
    19,884 Antigen processing and presentation of exogenous antigen 37.50 .002
    19,882 Antigen processing and presentation 32.20 < .001
    48,002 Antigen processing and presentation of peptide antigen 25.00 < .001
    2474 Antigen processing and presentation of peptide antigen via MHC class I 20.00 < .001
    6935 Chemotaxis 6.12 .005
    42,330 Taxis 6.12 .005
    6955 Immune response 5.22 < .001
    7610 Behavior 5.14 .002
    2376 Immune system process 4.08 < .001
    42,221 Response to chemical stimulus 3.83 .005
    50,896 Response to stimulus 3.48 < .001
GO terms over-represented among the genes negatively correlated with MN1 expression
    35,272 Exocrine system development 33.33 .005
    9953 Dorsal/ventral pattern formation 30.77 < .001
    42,384 Cilium biogenesis 22.22 .004
    42,742 Defense response to bacterium 17.95 < .001
    48,736 Appendage development 16.00 < .001
    35,108 Limb morphogenesis 16.00 < .001
    35,107 Appendage morphogenesis 16.00 < .001
    6334 Nucleosome assembly 15.38 < .001
    9617 Response to bacterium 15.22 .001
    31,497 Chromatin assembly 14.12 < .001
    35,113 Embryonic appendage morphogenesis 13.64 .003
    30,326 Embryonic limb morphogenesis 13.64 .003
    6333 Chromatin assembly or disassembly 10.92 < .001
    65,004 Protein-DNA complex assembly 10.57 < .001
    3002 Regionalization 10.34 .002
    7389 Pattern specification process 9.76 .001
    51,707 Response to other organism 8.41 < .001
    9607 Response to biotic stimulus 6.12 .002
    6325 Establishment and/or maintenance of chromatin architecture 5.98 < .001
    6323 DNA packaging 5.93 < .001
    7001 Chromosome organization and biogenesis (sensu Eukaryota) 5.19 < .001
    51,276 Chromosome organization and biogenesis 5.07 < .001
    65,003 Macromolecular complex assembly 3.82 .001
    6259 DNA metabolic process 3.64 .004
    7275 Multicellular organismal development 2.93 .003
    48,856 Anatomical structure development 2.83 .005
    32,502 Developmental process 2.76 < .001
    48,869 Cellular developmental process 2.63 .005
    30,154 Cell differentiation 2.63 .005

Abbreviation: GO, gene ontology.

Table A3.

Signature of 15 microRNA Probes Significantly Correlated With MN1 Expression Level, Grouped by Direction of Correlation

Target microRNA Probe Sequence Correlation Coefficient P
Probes positively correlated with MN1 expression
    hsa-miR-126 ACACTTCAAACTCGTACCGTGAGTAATAATGCGCCGTCCA 0.405 .002893
    hsa-miR-126 ACACTTCAAACTCGTACCGTGAGTAATAATGCGCCGTCCA 0.388 .004862
    hsa-miR-126* CGCTGGCGACGGGACATTATTACTTTTGGTACGCGCTGTG 0.541 .000001
    hsa-miR-126* GCTGGCGACGGGACATTATTACTTTTGGTACGCGCTGTGA 0.502 .000005
    hsa-miR-126* GACGGGACATTATTACTTTTGGTACGCGCTGTGACACTTC 0.482 .000012
    hsa-miR-129-5p CCCTTCGCGAATCTTTTTGCGGTCTGGGCTTGCTGTACAT 0.391 .000517
    hsa-miR-130b CTGGGAAGCAGTGCAATGATGAAAGGGCATCGGTCAGGTC 0.340 .002874
    hsa-miR-424 GAGGGGATACAGCAGCAATTCATGTTTTGAAGTGTTCTAA 0.346 .002367
Probes negatively correlated with MN1 expression
    hsa-miR-16 GTTCCACTCTAGCAGCACGTAAATATTGGCGTAGTGAAAT −0.332 .003575
    hsa-miR-16 CAATGTCAGCAGTGCCTTAGCAGCACGTAAATATTGGCGT −0.339 .002957
    hsa-miR-19a TGTAGTTGTGCAAATCTATGCAAAACTGATGGTGGCCTGC −0.342 .004595
    hsa-miR-20a TAAAGTGCTTATAGTGCAGGTAGTGTTTAGTTATCTACTG −0.324 .004543
    hsa-miR-100 TGAGGCCTGTTGCCACAAACCCGTAGATCCGAACTTGTGG −0.411 .000250
    hsa-miR-100 CCTGTTGCCACAAACCCGTAGATCCGAACTTGTGGTATTA −0.486 .000040
    hsa-miR-196a AGCTGATCTGTGGCTTAGGTAGTTTCATGTTGTTGGGATT −0.335 .004960

Footnotes

Supported in part by Grants No. CA101140, CA114725, CA31946, CA33601, CA16058, CA77658, CA35279, CA03927, and CA41287 from the National Cancer Institute, Bethesda, MD, and The Coleman Leukemia Research Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Guido Marcucci, Michael D. Radmacher, Clara D. Bloomfield

Financial support: Michael A. Caligiuri, Clara D. Bloomfield

Administrative support: Guido Marcucci, Michael A. Caligiuri, Clara D. Bloomfield

Provision of study materials or patients: Guido Marcucci, Ravi Vij, Bayard L. Powell, Jonathan E. Kolitz, Michael A. Caligiuri, Richard A. Larson, Clara D. Bloomfield

Collection and assembly of data: Guido Marcucci, Peter Paschka, Susan P. Whitman, Claudia D. Baldus, Andrew J. Carroll

Data analysis and interpretation: Christian Langer, Guido Marcucci, Kelsi B. Holland, Michael D. Radmacher, Kati Maharry, Peter Paschka, Susan P. Whitman, Krzysztof Mrózek, Claudia D. Baldus, Andrew J. Carroll, Clara D. Bloomfield

Manuscript writing: Christian Langer, Guido Marcucci, Kelsi B. Holland, Michael D. Radmacher, Kati Maharry, Peter Paschka, Susan P. Whitman, Krzysztof Mrózek, Clara D. Bloomfield

Final approval of manuscript: Christian Langer, Guido Marcucci, Kelsi B. Holland, Michael D. Radmacher, Kati Maharry, Peter Paschka, Susan P. Whitman, Krzysztof Mrózek, Claudia D. Baldus, Ravi Vij, Bayard L. Powell, Andrew J. Carroll, Jonathan E. Kolitz, Michael A. Caligiuri, Richard A. Larson, Clara D. Bloomfield

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