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.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Cytogenetic and molecular genetic characterization of KMT2A-PTD positive acute myeloid leukemia in comparison to KMT2A-Rearranged acute myeloid leukemia.Cancer Genet. 2020 Jan;240:15-22. doi: 10.1016/j.cancergen.2019.10.006. Epub 2019 Nov 1. Cancer Genet. 2020. PMID: 31698332
Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells.Blood. 2012 Aug 2;120(5):1118-29. doi: 10.1182/blood-2012-02-412379. Epub 2012 Jun 26. Blood. 2012. PMID: 22740449 Free PMC article.
High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis.Oncotarget. 2015 Oct 20;6(32):33217-25. doi: 10.18632/oncotarget.5202. Oncotarget. 2015. PMID: 26375248 Free PMC article.
[Functional role of DNMT3A mutation in acute myeloid leukemia].Rinsho Ketsueki. 2018;59(5):602-610. doi: 10.11406/rinketsu.59.602. Rinsho Ketsueki. 2018. PMID: 29877252 Review. Japanese.
[Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia].Rinsho Ketsueki. 2018;59(10):2260-2267. doi: 10.11406/rinketsu.59.2260. Rinsho Ketsueki. 2018. PMID: 30305534 Review. Japanese.
- MOST 103-2321-B-182-015, MOST 104-2321-B-182-005/Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- NHRI-EX103-10003NI/National Health Research Institutes (NHRI)
- MOHW103-TD-B-111-09/Ministry of Health and Welfare (Ministry of Health and Welfare, Taiwan)
- OMRPG380031, OMRPG3C0021, and 101-1409B/Chang Gung Memorial Hospital (CGMH)