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Background  Additional 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.    Methods  To 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.    Results  Co-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.    Conclusion  The 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.

RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia