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Acute myeloid leukemia (AML) with partial tandem duplication of  histone-lysine N-methyltransferase 2A  ( KMT2A -PTD) is a subtype of AML and is associated with adverse survival, yet the molecular pathogenesis of  KMT2A -PTD is not fully understood. DNA methyltransferase 3A ( DNMT3A ) is mutated in various myeloid neoplasms including AML, especially at the Arg882. Recently, it has been found that  DNMT3A  mutations frequently coexisted with  KMT2A -PTD and are associated with inferior outcomes. We aimed to understand the biological role of DNMT3A mutation in  KMT2A -PTD-positive cells. Herein, we found that overexpression of  DNMT3A  mutants (MT) in  KMT2A -PTD-positive EOL-1 cells augmented cell proliferation and clonogenicity. Serial colony replating assays indicated that  DNMT3A -MT increased the self-renewal ability of  Kmt2a -PTD-expressing mouse bone marrow cells with immature morphology. At 10 months post bone marrow transplantation, mice with the combined  Kmt2a- PTD and  DNMT3A -MT showed hepatosplenomegaly and leukocytosis with a shorter latency compared to control and  DNMT3A -wild-type. Gene expression microarray analyses of bone marrow samples from human AML with  KMT2A -PTD/ DNMT3A -MT showed a stem cell signature and myeloid hematopoietic lineage with dysregulation of  HOXB  gene expression. In addition, human bone marrow AML cells carrying  KMT2A -PTD/ DNMT3A -MT showed abnormal growth and augmented self-renewal activity in primary cell culture. The present study provides information underlying the pathogenic role of DNMT3A-MT with KMT2A-PTD in proliferating advantage with augmentation of self-renewal activity in human leukemia, which may help to better understand the disease and to design better therapy for AML patients with these mutations.

oncogenesis

DNMT3A mutants provide proliferating advantage with augmentation of self-renewal activity in the pathogenesis of AML in KMT2A-PTD-positive leukemic cells