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Prognostic impact of ASXL1 mutations in chronic phase chronic myeloid leukemia.

ABSTRACT: While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and accelerated phase (40%) CML patients, whereas RUNX1 (20%) was the most common mutation in blast phase. Compared with wild-type ASXL1, CP-CML with mutant ASXL1 was associated with worse event-free survival (EFS) (median of 32.8 vs 88.3 months; P = 0.002) and failure-free survival (median of 13.8 vs 57.8 months; P = 0.04). In a multivariate analysis, ASXL1 mutation was the only independent risk factor associated with worse EFS in chronic phase CML with a hazard ratio of 4.25 (95% CI 1.59-11.35, P = 0.004). In conclusion, mutations in ASXL1 are associated with worse outcomes when detected in chronic phase CML.

SUBMITTER: Bidikian A

PROVIDER: S-EPMC9616867 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Prognostic impact of ASXL1 mutations in chronic phase chronic myeloid leukemia.

Bidikian Aram A Kantarjian Hagop H Jabbour Elias E Short Nicholas J NJ Patel Keyur K Ravandi Farhad F Sasaki Koji K Issa Ghayas C GC

Blood cancer journal 20221028 10

While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and acc ...[more]

PMID: 36307398

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Project description:BackgroundAdditional sex combs-like 1 (ASXL1) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations (RUNX1-MT) coexisted with ASXL1-MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1-mutated leukemia, however, remains unclear.MethodsTo evaluate the leukemogenic role of RUNX1-MT in ASXL1-mutated cells, we co-expressed RUNX1-MT (R135T) and ASXL1-MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model.ResultsCo-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1-mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1-MT or ASXL1-MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells.ConclusionThe present study demonstrated the biological and functional evidence for the critical role of RUNX1-MT in ASXL1-mutated leukemia in the pathogenesis of myeloid malignancies.

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Prognostic impact of ASXL1 mutations in chronic phase chronic myeloid leukemia.

Publications

Prognostic impact of ASXL1 mutations in chronic phase chronic myeloid leukemia.

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