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A novel RUNX1::EWSR1 gene fusion in a young male acute myeloid leukemia (AML) patient: A case report

Cancer Genetics and Therapeutics
  • Primary Categories:
    • Cancer
  • Secondary Categories:
    • Cancer
Introduction
RUNX1, encoding the alpha subunit of the core-binding factor (CBF), is essential for normal hematopoiesis. RUNX1 mutations and fusions are frequently observed in hematologic malignancies. The RUNX1::RUNX1T1 fusion, resulting from the t(8;21)(q22;q22) translocation, is a well-characterized and defining genetic abnormality in acute myeloid leukemia (AML). Other common RUNX1 fusions include ETV6::RUNX1 fusion in pediatric acute lymphoblastic leukemia and RUNX1::MECOM fusion in therapy-related myeloid neoplasm. While various rare RUNX1 fusions with other partners have been described, the RUNX1::EWSR1 fusion identified in this patient has not been previously reported.

Case Presentation


A 26-year-old male presented with a three-week history of fatigue, easy bruising, and gingival bleeding prompting further hematologic evaluation.


 








Diagnostic Workup
Complete blood count revealed leukocytosis with white blood cell (WBC) count of 46.8 x 10³/µL, anemia with hemoglobin of 8.7 g/dL, and thrombocytopenia with platelets of 17 x 10³/µL. The WBC differential showed 78% blasts. Diagnostic bone marrow biopsy indicated AML with myelodysplasia-related changes in hypercellular bone marrow (90%) with decreased trilineage hematopoiesis, including dysgranulopoiesis and dysmegakaryopoiesis, and 67% blasts. Flow cytometry detected 75% immunophenotypically aberrant myeloid blasts with expression of monocytic markers CD11b, CD33, and CD64. Immunohistochemistry for CD42b highlighted a population of small, hypolobate megakaryocytes.

Cytogenetic karyotyping analysis of the bone marrow revealed two cell clones: one with a balanced t(2;21)(p23;q22) translocation and another with additional trisomies of chromosomes 10, 12, 21, and 22 (ISCN: 46,XY,t(2;21)(p23;q22)[14]/50,XY,t(2;21)(p23;q22),+10,+12,+21,+22[6]). Interphase FISH showed that approximately 50% of cells had an additional copy of RUNX1, and 40% had three extra copies of RUNX1. RNA-seq analysis identified a novel RUNX1::EWSR1 fusion, joining exon 7 of RUNX1 (N-terminus) with exon 10 of EWSR1 (C-terminus). AML Mutation Profiling assay detected a CBL mutation (c.1096-1G>T, VAF 11.5%) and two NRAS mutations (p.Q61R, VAF 31.2%; p.Q61K, VAF 12.5%) in trans configuration. To further characterize the RUNX1::EWSR1 fusion, metaphase and G-banded FISH were performed. Metaphase FISH with RUNX1 probe revealed one or two extra RUNX1 signals on the long arm of chromosome 22, while metaphase FISH for EWSR1 and G-banded FISH for 22q subtelomeric probe showed no abnormal localization of EWSR1 and 22q subtelomeric region. These findings suggest that the RUNX1::EWSR1 fusion likely arose from a cryptic insertion of RUNX1 on chromosome 22 rather than a translocation involving chromosomes 21 and 22 or a three-way translocation with chromosomes 2, 21, and 22. 

Treatment and Management
The patient received initial intensive induction 7+3 chemotherapy (7 days of cytarabine and 3 days of daunorubicin). A follow-up bone marrow biopsy showed refractory disease prompting a re-induction with FLAG-Ida chemotherapy (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (G-CSF)), after which a complete remission was achieved. 

Outcome and Follow-Up
His karyotyping, FISH and AML Mutation Profiling studies were unremarkable. A consolidative allogeneic stem cell transplant is planned as the definitive therapy based on high-risk, primary refractory disease.

Discussion
This represents the first reported AML case with a novel RUNX1::EWSR1 fusion. RUNX1 fusions generally contain either the N-terminal runt-homology domain (RHD) alone or both the RHD and C-terminal transactivation domain (TAD) of RUNX1. EWSR1 fusions are common alterations seen in bone and soft tissue tumors, which typically involve the N-terminal portion of EWSR1 (at least exons 1-7) fused to various C-terminal partners. In this patient, a novel RUNX1::EWSR1 fusion was identified, juxtaposing exon 7 of RUNX1 with exon 10 of EWSR1, producing a chimeric protein containing the RHD domain of RUNX1 and C-terminus of EWSR1. 

Conclusion
RUNX1::EWSR1 fusion protein may exert a dominant-negative effect on wild-type RUNX1 and contribute to leukemogenesis. This case demonstrates the critical role of comprehensive cytogenetic and molecular genetic analyses in revealing complex genomic alterations in hematologic malignancies.

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