Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis

Haematologica. 2022 Jan 1;107(1):86-99. doi: 10.3324/haematol.2020.271619.


Chromosomal translocations involving KMT2A gene are one of the most common genetic alterations found in pediatric acute myeloid leukemias (AML) although the molecular mechanisms that initiate the disease remain incompletely defined. To elucidate these initiating events we have used a human model system of AML driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin accessibility at each stage of our model system and correlated these with expression changes. We observe the development of a profound hypomethylation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem cell associated genes along with skewed expression in other genes such as S100A8/9 implicated in leukemogenesis. In addition, early increases in the expression of the lysine demethylase KDM4B was functionally linked to these expression changes as well as other key transcription factors. Remarkably, our ATAC-seq data showed that there were relatively few leukemiaspecific changes and the vast majority corresponded to open chromatin regions and transcription factor clusters previously observed in other cell types. Integration of the gene expression and epigenetic changes revealed the adenylate cyclase gene ADCY9 as an essential gene in KM3-AML, and suggest the potential for autocrine signalling through the chemokine receptor CCR1 and CCL23 ligand. Together, our results suggest that KM3 induces subtle changes in the epigenome while co-opting the normal transcriptional machinery to drive leukemogenesis.

MeSH terms

  • Adenylyl Cyclases
  • Child
  • DNA Methylation
  • Epigenesis, Genetic*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Jumonji Domain-Containing Histone Demethylases
  • Leukemia, Myeloid*
  • Leukemia, Myeloid, Acute* / genetics
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein
  • Translocation, Genetic


  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human
  • Histone-Lysine N-Methyltransferase
  • Adenylyl Cyclases
  • adenylate cyclase 9

Grants and funding

Funding: This work was supported by grants from the Cole Foundation (to TM, fellowship), the Impact Grant of the Canadian Cancer Society in collaboration with The Cole Foundation, Molson Foundation, R. Howard Webster Foundation, Mirella and Lino Saputo Foundation, Fonds de Recherche du Quebec - Santé, Faculté de Médicine, Université de Montréal, Letko Brosseau, Birks Family Foundation, Maryse and William Brock, CHU Sainte-Justine Foundation, Montreal Children's Hospital Foundation, Morris and Rosalind Goodman Family Foundation, Zeller Family Foundation, David H. Laidley Foundation, Drummond Foundation, and the Henry and Berenice Kaufmann Foundation (grant 705047-IMP-17; to BW, FB, SC), and the Leukemia & Lymphoma Society of Canada (to FB). Human leukemia specimens were collected and analyzed by the Banque de Cellules Leucémiques du Québec, supported by the Cancer Research Network of the Fonds de Recherche du Québec en Santé.