Table 2.
Clinical relevance of cytogenetic abnormalities and gene mutations in MDS/MPN.
| MDS/MPN Subtype | Diagnosis | Prognosis |
|---|---|---|
| CMML | -WHO [1]: presence of mutations in genes often associated with CMML (TET2, SRSF2, ASXL1, SETBP1) in the proper clinical contest can be used to support diagnosis -Associated with the following gene mutation combinations: TET2-SRSF2, biallelic TET2, SRSF2-RUNX1 [2,4,30] |
Cytogenetics -Three cytogenetic stratification systems have been proposed [23,24,25] -Recurrent findings: • Low risk karyotypes: normal karyotype, isolated loss of Y • High risk karyotypes: chr7 abnormalities, complex karyotype, monosomal karyotype Gene mutations: -Unfavorable outcome: mutations in ASXL1, RUNX1, NRAS and SETBP1 [2,30,31] -Favorable outcome: TET2 mutations, especially in the absence of ASXL1 mutations (TET2MUT/ASXL1WT). These patients also show better response to HMA [32,33,34]. Prognostic stratification: -GFM Model [2], stratification in 3 risk groups based on: Age > 65 years; Hb < 10 g/dL in females and <11 g/dL in males; WBC > 15 × 109/L; Platelet count < 100 × 109/L; ASXL1 mutations -Mayo Molecular Model (MMM) [31], stratification in 4 risk groups based on: Hb < 10 g/dL; AMC > 10 × 109/L; Platelet count < 100 × 109/L; Presence of circulating IMCs; ASXL1 mutations -CPSS-Mol [30], stratification in 4 risk groups based on: WBC ≥ 13 × 109; BM blasts ≥ 5%; RBC transfusion dependency; Genetic risk group (includes CMML-specific cytogenetic risk stratification [23] and mutations in ASXL1, RUNX1, NRAS and SETBP1). |
| aCML | -Associated with the following gene mutation combinations: ASXL1/SETBP1, SETBP1/SRSF2, ASXL1/EZH2, RUNX1/EZH2 [3,4,35] | Unfavorable outcome: mutations in TET2, RUNX1, NRAS and CUX1 [3,4] Prognostic stratification: Mayo Prognostic Model for aCML [3], stratification in 2 risk groups based on: Age > 67 years; Hb < 10 g/dL; TET2 mutations |
| MDS/MPN-RS-T | -WHO [1]: presence of a SF3B1 mutation. -Associated with the following gene mutation combinations: SF3B1, either alone or in combination with DNMT3A or JAK2, or DNMT3A/JAK2 [4,26,36] |
Unfavorable outcome: -Presence of altered karyotype [4,26] -Mutations in ASXL1, SETBP1, EZH2 [4,26] Prognostic stratification: Mayo Prognostic Model for MDS/MPN-RS-T [26], stratification in 3 risk groups based on: Hb < 10 g/dL; Abnormal karyotype; mutations in ASXL1 or SETBP1 |
| MDS/MPN-U | - | Unfavorable outcome: -Presence of chr7 abnormalities and complex karyotypes [19] -Mutations in ASXL1, CBL, CEBPA, EZH2, STAG2, TP53 [4,27,37] Prognostic stratification: -Genomics-based stratification system (Figure 4), classification in 5 subtypes with prognostic relevance based on mutational profile [4] |
| JMML | -WHO [1]: presence of (1 finding sufficient): • Somatic mutation: PTPN11, KRAS, NRAS • Clinical diagnosis of NF1 or NF1 mutation • Germline CBL mutation CBL LOH |
Prognostic stratification: According to the methylation level, three groups that correlate molecular features and clinical outcome have been proposed [38]: • High: characterized by somatic PTPN11 mutations and poor clinical outcome • Intermediate: enriched in somatic KRAS mutations and monosomy 7 • Low: characterized by somatic NRAS and CBL mutations and a favorable prognosis |
Abbreviations: aCML: atypical chronic myeloid leukemia; AMC: absolute monocyte count; chr: chromosome; CMML: chronic myelomonocytic leukemia; CPSS-Mol: molecular CMML-specific prognostic scoring system; GFM: Groupe Francophone des Myelodysplasies; Hb: Hemoglobin; HMA: hypomethylating agents; HSCT: hematopoietic stem cell transplantation; IMCs: immature myeloid cells; JMML: juvenile myelomonocytic leukemia; LOH: loss of heterozygosity; MDS/MPN-RS-T: myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis; MDS/MPN-U: myelodysplastic/myeloproliferative neoplasm unclassifiable; RBC: red blood cells; WBC: white blood cell count; WHO: World Health Organization.