TIF1/TRIM24::FGFR1-rearranged myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusion presenting as mixed-phenotype acute leukemia: a case report

Abstract

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions are rare aggressive malignancies. FGFR1-rearranged cases are particularly high-risk. Among FGFR1 fusion partners, TIF1/TRIM24::FGFR1 is exceptionally rare.

We report a 33-year-old woman presenting with fever, skin bruising, leukocytosis, thrombocytopenia, and circulating blasts. Bone marrow and flow cytometry identified abnormal B-lymphoblasts, myeloid blasts, and monocytic populations, supporting a mixed-phenotype acute leukemia presentation. Cytogenetics detected t(8;7)(p11;q34) translocation. Whole-transcriptome sequencing identified a TIF1/TRIM24::FGFR1 fusion transcript, confirmed by Sanger sequencing and FISH. RUNX1 missense mutation was also detected. The patient achieved complete remission after induction chemotherapy. However, after discontinuation of therapy and refusal of allo-HSCT, she relapsed rapidly with clonal evolution. A second remission was transient, and the patient died of cerebral hemorrhage.

This case highlights the aggressive biology of TIF1/TRIM24::FGFR1-rearranged MLN-TK, the limitation of conventional chemotherapy, and the potential value of fusion-specific monitoring. Early allo-HSCT should be considered once remission is achieved, and FGFR1-directed therapy may represent a potential option in selected patients. However, clinical evidence remains limited and further studies are required.

1. Introduction

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, currently classified as MLN-TK, comprise a group of rare hematologic malignancies driven by constitutively activated tyrosine kinase signaling. Among them, neoplasms with FGFR1 rearrangement represent an aggressive subgroup that was historically known as 8p11 myeloproliferative syndrome[1,2]. The 2022 World Health Organization classification recognizes FGFR1-rearranged neoplasms within MLN-TK, emphasizing their distinctive genetic basis and heterogeneous clinicopathologic presentations[3,4].

FGFR1-rearranged MLN-TK can manifest as myeloproliferative neoplasm, acute myeloid leukemia, B- or T-lymphoblastic leukemia/lymphoma, or mixed-phenotype acute leukemia. The underlying genetic events involve translocations, insertions, or inversions affecting chromosome 8p11–12, generating pathogenic FGFR1 fusion oncogenes. These fusions lead to ligand-independent activation of FGFR1 kinase activity and downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and STAT pathways.

More than 40 FGFR1 fusion partners have been described [1,5], with several recurrent fusions such as ZNF198::FGFR1, BCR::FGFR1, and CEP110::FGFR1 [1]. In contrast, TIF1/TRIM24::FGFR1 is exceedingly rare, and only a few cases have been reported. Detailed clinical, cytogenetic, molecular, therapeutic, and measurable residual disease data remain limited.

Here, we describe a young woman with TIF1/TRIM24::FGFR1-rearranged MLN-TK presenting as mixed-phenotype acute leukemia (MPAL), accompanied by RUNX1 mutation, dynamic clonal evolution, and fusion transcript-based disease monitoring. This case further illustrates the aggressive clinical course of this rare entity and underscores the need for early definitive and targeted therapeutic strategies.

2. Case presentation

A 33-year-old female was admitted to our hospital on Nov. 2nd 2023 because of fever and skin bruising (shown in Fig. 1A). Physical examination showed scattered ecchymoses, without lymphadenopathy, hepatosplenomegaly, or central nervous system symptoms.

Fig. 1.

Clinical and laboratory features of the patient.

A. Clinical course of the patient, including treatment, remission, relapse, and survival.

B. Wright–Giemsa staining of bone marrow aspirate smears (upper two) and peripheral blood smears (bottom two) showing blast proliferation with mixed morphologic features.

C. Flow cytometric analysis demonstrating distinct abnormal cellular populations, including B-lymphoblasts, myeloid blasts, and aberrant monocytic populations.

Initial complete blood count showed leukocytosis and thrombocytopenia: white blood cell count, 34.88 × 10⁹/L; hemoglobin, 136 g/L; and platelet count, 34 × 10⁹/L. Peripheral blood differential count revealed 64% blasts. Bone marrow aspiration showed hypercellular marrow with 67.5% blasts.

Morphologic evaluation of peripheral blood and bone marrow smears revealed two major abnormal populations (shown in Fig. 1B). One population consisted predominantly of monoblast-like cells with large cell size, high nuclear-to-cytoplasmic ratio, indented or convoluted nuclei, partially loosened chromatin, indistinct nucleoli, deeply basophilic cytoplasm, and occasional cytoplasmic vacuolation. A small number of promonocytes with occasional pink granules were also observed. The second population consisted of lymphoblast-like cells with regular contours, round nuclei, fine chromatin, nuclear notching, and scant cytoplasm. No significant eosinophilia was observed.

Flow cytometry results detected four different groups of abnormal cells (shown in Fig. 1C). The first population, accounting for 24.38% of nucleated cells, was consistent with abnormal B-lymphoblasts and expressed CD34, CD22, cytoplasmic CD79a, CD19, CD123, and partial CD13, while lacking CD117, CD33, MPO, CD3, CD7, CD10, CD20, CD56, and monocytic markers. The second population, accounting for 13.62% of nucleated cells, represented abnormal myeloid blasts expressing CD34, partial CD117, CD123, partial HLA-DR, partial CD33, and partial CD13, but lacking MPO and lymphoid markers. Two additional abnormal monocytic populations were detected, accounting for 12.01% and 15.80% of nucleated cells, respectively. Both expressed HLA-DR, CD33, CD123, CD85K, and CD85J, with variable expression of CD14, CD36, and CD64.

Conventional cytogenetic analysis demonstrated a complex karyotype involving abnormalities of chromosomes 7 and 8p11: 46, XX, add(7)(q32), add(8)(p11)[3] /73∼78, XXX, +X, +2, +3, −7, add(7)(q32), add(8)(p11), +9, +10, +12, +17, +18, +19, +21[13] /90, XXXX, add(7)(q32) × 2, add(8)(p11) × 2, −18, −22[3] /46, XX[1] (shown in Fig. 2A).

Fig. 2.

Cytogenetic and molecular characterization of TIF1/TRIM24::FGFR1 fusion.

A. G-banded karyogram of bone marrow cells showing chromosomal abnormalities involving chromosomes 7 and 8p11.

B. Sanger sequencing of the RT-PCR product confirming the TIF1/TRIM24::FGFR1 fusion junction.

C. Schematic representation of the fusion transcript showing fusion of TRIM24 exon 9 to FGFR1 exon 10.

D. Fluorescence in situ hybridization analysis using custom-designed probes confirming the TIF1/TRIM24::FGFR1 rearrangement.

Targeted genomic analysis detected a RUNX1 missense mutation, c.319C>T; p.R107C, located in exon 4 (chr21:36,259,172), with a variant allele frequency of 86.30%. Copy-number variation (CNV) analysis revealed increased copy number involving a region of KMT2A at 11q23.3, spanning exons 2–10 (approximately 16.6 kb in length).

Whole-transcriptome RNA sequencing identified a TIF1/TRIM24::FGFR1 fusion transcript, generated by the fusion of exon 9 of the TRIM24 gene (NM_015905) to exon 10 of the FGFR1 gene (NM_023110). The fusion was further confirmed by Sanger sequencing (shown in Fig. 2B) and fluorescence in situ hybridization (FISH) using custom-designed probes (shown in Fig. 2C). A fusion-specific RT-qPCR assay was established for measurable residual disease monitoring. At diagnosis, the TIF1/TRIM24::FGFR1 transcript level was 7.20%.

The patient was diagnosed with myeloid/lymphoid neoplasm with tyrosine kinase gene fusion, FGFR1-rearranged. Nevertheless, based on the integrated morphologic, immunophenotypic, cytogenetic, and molecular findings, according to WHO/ICC lineage assignment criteria for acute leukemias of ambiguous lineage[4], the abnormal B-lymphoblast population fulfilled B-lineage assignment by expression of CD19 together with additional B-lineage markers, including CD22 and cytoplasmic CD79a. In parallel, the presence of abnormal myeloid blasts and abnormal monocytic populations showing monocytic differentiation, including expression of CD14 and CD64 together with monoblast/promonocyte morphology, supported myeloid/monocytic lineage involvement. The integrated findings supported a diagnosis of FGFR1-rearranged MLN-TK presenting with MPAL.

Given the prominent B-lymphoblast component and the MPAL phenotype, an ALL-like induction strategy was selected. The treatment plan was to achieve remission with lymphoid-based induction and consolidation therapy followed by early allo-HSCT if feasible. The patient received induction chemotherapy with a VDP regimen consisting of vincristine 2 mg/m² on days 1, 8, 15, and 22; daunorubicin 40 mg/m² on days 1–3; and prednisone 1 mg/kg daily on days 1–28, tapered from day 21.

Complete remission was achieved on day 28. Bone marrow evaluation showed no morphologic evidence of leukemia, flow cytometry did not detect residual leukemic cells, RT-qPCR showed undetectable TIF1/TRIM24::FGFR1 transcript, and cytogenetic analysis revealed a normal female karyotype, 46,XX [20].

The patient subsequently received consolidation therapy with a revised Hyper-CVAD-B regimen consisting of methotrexate 1 g/m² on day 1 and cytarabine 2 g/m² every 12 h on days 2–3. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was strongly recommended. However, the patient declined allo-HSCT and discontinued treatment for personal reasons.

Two months later, she experienced hematologic relapse. Bone marrow examination showed 78.5% blasts. Flow cytometry revealed an immunophenotype similar to that observed at diagnosis. Cytogenetic analysis demonstrated clonal evolution with a complex karyotype and newly acquired del(13)(q14q22): 47, XX, add(7)(q32) × 2, add(8)(p11), +del(13)(q14q22)[13]/48, idem, +8[3]/ 76<3n>, XXX, +X, +1, −3, +5, +5, add(7)(q32) × 3, add(8)(p11), +9, −11, +del(13)(q14q22), +16, +18, +20[1]/ 85∼93<4n>, XX, -X, -X, −4, −5, −6, add(7)(q32) × 3, add(8)(p11) × 2, −9, +del(13)(q14q22), +18, −19, −20, −22[cp2]/ 46, XX[1]. (Table 1).

Table 1.

Changes in the patient's chromosomal karyotype and fusion gene levels at different time points.

Time points	Karyotype	TIF1:: FGFR1
Onset	46, XX, add(7)(q32), add(8)(p11)[3] / 73∼78, XXX, +X, +2, +3, −7, add(7)(q32), add(8)(p11), +9, +10, +12, +17, +18, +19, +21[13] / 90, XXXX, add(7)(q32) × 2, add(8)(p11) × 2, −18, −22[3] / 46, XX[1]	7.20%
CR1	46,XX[20]	0
Relapse	47, XX, add(7)(q32)x2, add(8)(p11), +del(13)(q14q22)[13]/ 48, idem, +8[3]/ 76<3n>, XXX, +X, +1, −3, +5, +5, add(7)(q32)X3, add(8)(p11), +9, −11, +del(13)(q14q22), +16, +18, +20[1]/ 85∼93<4n>, XX, -X, -X, −4, −5, −6, add(7)(q32)X3, add(8)(p11)X2, −9, +del(13)(q14g22), +18, −19, −20, −22[cp2]/ 46, XX[1]	21.89%
CR2	N/A	2.06%

Bold font indicates newly emerging additional chromosomal abnormalities.

The TIF1/TRIM24::FGFR1 transcript level increased to 21.89% by RT-qPCR. The patient received cytarabine 2 g/m² every 12 h on days 1–3 and achieved a second complete remission. However, molecular remission was not achieved; the TIF1/TRIM24::FGFR1 transcript decreased only to 2.06%. One week later, the disease relapsed again. The patient died of cerebral hemorrhage on May 7th 2024.

3. Discussion

FGFR1-rearranged MLN-TK is a rare but highly aggressive hematologic neoplasm with diverse clinical presentations. The present case is notable for several reasons. First, the disease was driven by the exceptionally rare TIF1/TRIM24::FGFR1 fusion. Second, it presented as MPAL with B-lymphoblastic, myeloid blast, and aberrant monocytic components. Third, comprehensive molecular monitoring showed that conventional chemotherapy achieved an initial deep remission, but relapse occurred rapidly with clonal evolution and re-emergence of the fusion transcript.

Previous studies have shown that FGFR1-rearranged MLN-TK may present with diverse clinicopathologic phenotypes, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), and MPAL. Several FGFR1-rearranged MPAL or mixed-lineage acute leukemia cases have been reported, particularly involving BCR::FGFR1. Khodadoust et al. described a patient with FGFR1-rearranged MPAL who showed clinical activity to ponatinib[6], whereas Morishige et al. reported BCR::FGFR1-positive 8p11 myeloproliferative syndrome presenting as trilineage acute leukemia/lymphoma and successfully treated with cord blood transplantation[7]. These cases indicate that FGFR1 fusion-positive disease may originate from an early progenitor capable of multilineage differentiation. Consistent with these observations, our case demonstrated both B-lymphoid and myeloid/monocytic components. Nevertheless, the present case is distinct because it was associated with the rare TIF1/TRIM24::FGFR1 fusion.

The TRIM24 gene, also known as TIF1α, encodes a transcriptional regulator involved in chromatin remodeling, transcriptional regulation, cell differentiation, mitosis, ubiquitination-related processes, and DNA damage responses[8]. In TIF1/TRIM24::FGFR1-rearranged neoplasms, the regulatory domains of TRIM24 are fused to the intracellular tyrosine kinase domain of FGFR1 [9]. This rearrangement likely promotes constitutive dimerization and ligand-independent kinase activation, leading to persistent downstream signaling through pathways such as RAS/MAPK, PI3K/AKT, and STAT [10,11]. Such aberrant signaling may contribute to multilineage hematopoietic transformation, explaining the heterogeneous and mixed-lineage phenotype observed in this patient.

Only a small number of TIF1/TRIM24::FGFR1-rearranged cases have been described in the literature. Reported phenotypes include AML, CMML, B-LBL, and now MPAL (Table 2). Although the number of cases remains limited, available data suggest that this fusion is associated with aggressive clinical behavior and poor long-term outcome. In our patient, chemotherapy induced complete remission with disappearance of the fusion transcript, but remission was short-lived after discontinuation of therapy. At relapse, the disease showed increasing fusion transcript burden and acquisition of additional cytogenetic abnormalities, indicating clonal evolution.

Table 2.

Clinical outcomes of EMS patients with TIF1/TRIM24::FGFR1.

Cases	Age, gender	Common phenotype	karyotype	Additional mutation	Sensitivity to chemotherapy	HSCT	FGFR-i	Best efficacy	PFS (m)	OS (m)	location
Byun et al. [9]	31, F	AML	47,XX,+21[8]/46,XX,del(?9)(q10),i(9) (q10)[7]/46,XX[5]	N/A	Yes	Plan	No	CR	46	N/A	Korean
Belloni et al. [10]	49, F	AML	N/A	N/A	No	No	No	-	-	0.6	Italy
Guzailinuer et al. [11]	71, M	CMML	Normal	U2AF1	Yes	No	No	CR	N/A	N/A	China
Cho et al. [6]	2, M	B-LBL	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	Korean
The current case	33, F	MPAL	See Table 1	RUNX1	Yes	No	No	CR	4	6	China

Abbreviations: EMS, eosinophilia-associated myeloid/lymphoid neoplasm syndrome; AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; B-LBL, B-lymphoblastic lymphoma; MPAL, mixed-phenotype acute leukemia; HSCT, hematopoietic stem cell transplantation; FGFR-i, fibroblast growth factor receptor inhibitor; CR, complete remission; PFS, progression-free survival; OS, overall survival; m, months; F, female; M, male; N/A, not available.

The concurrent RUNX1 p.R107C mutation may have contributed as a possible cooperating or adverse genetic event. RUNX1 is a key hematopoietic transcription factor required for normal blood cell differentiation. Somatic RUNX1 mutations are frequently observed in myeloid malignancies and are associated with impaired differentiation, increased self-renewal, and adverse clinical outcome [12,13]. However, the precise biological impact of this specific RUNX1 variant cannot be determined from a single case and requires further functional investigation.

This case also demonstrates the value of fusion-specific molecular monitoring. At diagnosis, the TIF1/TRIM24::FGFR1 transcript level was 7.20%. It became undetectable during first complete remission and increased to 21.89% at relapse. After salvage cytarabine therapy, the transcript decreased to 2.06%, but residual positivity was followed by rapid clinical relapse. These findings suggest that fusion-specific RT-qPCR appeared to reflect disease burden and preceded rapid clinical relapse when residual positivity persisted after salvage therapy. However, this observation is based on a single case, and its broader clinical utility requires validation in additional cases.

Notably, significant eosinophilia was not observed in the present case. Although eosinophilia is a characteristic feature of this disease group, it is not uniformly present in FGFR1-rearranged MLN-TK, especially when patients present with leukemic transformation or acute leukemia. Previous reviews and case series of 8p11 myeloproliferative syndrome/FGFR1-rearranged MLN-TK have also documented heterogeneous hematologic presentations, including cases without prominent eosinophilia [[3], [4], [5],14]. Therefore, the absence of eosinophilia does not exclude the diagnosis when a pathogenic FGFR1 rearrangement is demonstrated together with compatible clinicopathologic findings.

Therapeutically, FGFR1-rearranged MLN-TK remains challenging. The disease portends an exceptionally poor prognosis, with contemporary studies reporting median overall survival of 14.6 months. Conventional chemotherapy regimens yield transient morphologic remission in <25% of cases, with universal relapse within 9 months due to intrinsic chemo-resistance [15,16]. Allo-HSCT is currently considered the most effective potentially curative approach and should be pursued early when feasible [7,17]. In the present case, allo-HSCT was recommended after the first complete remission but was declined, and the disease relapsed rapidly.

Targeted inhibition of FGFR1 represents a biologically rational therapeutic strategy [6]. However, clinical evidence in FGFR1-rearranged hematologic neoplasms remains limited compared with solid tumors and is derived mainly from case reports, small series, and early-phase studies [18,19]. Therefore, FGFR inhibitors should not be overinterpreted as established standard therapy in this setting. Their potential roles as induction therapy, salvage therapy, maintenance therapy, or bridge to allo-HSCT require further investigation.

In summary, this case expands the clinical spectrum of TIF1/TRIM24::FGFR1-rearranged MLN-TK and highlights the aggressive nature of this rare entity. Comprehensive genomic profiling is essential for accurate diagnosis, risk stratification, therapeutic planning, and measurable residual disease monitoring. Early allo-HSCT should be considered once remission is achieved, and FGFR1-targeted therapy may represent a promising option for patients with relapsed, refractory, or transplant-ineligible disease.

4. Conclusion

We report a rare case of TIF1/TRIM24::FGFR1-rearranged MLN-TK presenting as MPAL. Although significant eosinophilia was absent, the diagnosis was supported by the pathogenic FGFR1 rearrangement and the multilineage leukemic phenotype. The patient achieved an initial molecular remission after chemotherapy but relapsed rapidly with clonal evolution and increasing fusion transcript levels. This case emphasizes the aggressive behavior of FGFR1-rearranged MLN-TK, the limited durability of conventional chemotherapy, and the importance of considering early allo-HSCT once remission is achieved. Fusion-specific RT-qPCR may be a potential tool for individualized disease monitoring, but further validation is required. FGFR1-directed therapies represent a biologically rational strategy, although clinical evidence in hematologic neoplasms remains limited and warrants further investigation.

Ethics declaration

The authors have NOT obtained informed consent from participants or their legal representatives. Written informed consent could not be obtained because the patient described in this case report had died. All case-related data were anonymized, and any potentially identifiable personal or private information was removed. The clinical details and images included in this report are presented solely for academic and medical purposes and do not contain information that could directly identify the patient. Therefore, the requirement for written informed consent was waived.

This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place.

The Peking University People's Hospital granted an exemption. The authors provided the following explanation: Written informed consent could not be obtained because the patient described in this case report had died. All case-related data were anonymized, and any potentially identifiable personal or private information was removed. The clinical details and images included in this report are presented solely for academic and medical purposes and do not contain information that could directly identify the patient. Therefore, the requirement for written informed consent was waived.

This research follows the CARE guidelines and the CARE checklist.

Funding

No specific funding was received for this study.

CRediT authorship contribution statement

Rong Wei: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Conceptualization. Shasha Zhao: Writing – original draft, Investigation, Data curation. Yan Wei: Writing – original draft, Methodology, Data curation. Chengcheng Yan: Writing – original draft, Methodology, Data curation. Qian Jiang: Writing – review & editing, Validation, Supervision, Project administration.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.