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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):86-99
Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis
Thomas Milan,1 Magalie Celton,1 Karine Lagacé,1 Élodie Roques,1 Safia Safa-Tahar-Henni,1 Eva Bresson,2,3 Anne Bergeron,2,3 Josée Hebert,4,5 Soheil Meshinchi,6 Sonia Cellot,7 Frédéric Barabé2,3,8 and Brian T. Wilhelm1,5
1Laboratory for High Throughput Biology, Institute for Research in Immunology and Cancer, Montréal, Québec, Canada; 2Centre de Recherche en Infectiologie du CHUL, Centre de Recherche du CHU de Québec Université Laval, Québec City, Québec, Canada; 3CHU de Québec Université Laval Hôpital Enfant-Jésus, Québec City, Québec, Canada; 4Division of Hematology-Oncology and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada; 5Department of Medicine, Université de Montréal, Montréal, Québec, Canada; 6Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, PA, USA; 7Department of Pediatrics, Division of Hematology, Ste-Justine Hospital, Montréal, Québec, Canada and 8Department of Medicine, Université Laval, Quebec City, Québec, Canada
ABSTRACT
Chromosomal translocations involving the KMT2A gene are among the most common genetic alterations found in pediatric acute myeloid leukemias although the molecular mechanisms that initiate the disease remain incompletely defined. To elucidate these initiating events we used a human model system of acute myeloid leukemia driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin acces- sibility at each stage of our model system and correlated these with expres- sion changes. We observed the development of a pronounced hypomethyl- ation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem-cell-associated genes and skewed expression of other genes, such as S100A8/9, implicated in leuke- mogenesis. 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-sequenc- ing data showed that there were relatively few leukemia-specific changes and that 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 that the adenylate cyclase gene ADCY9 is an essential gene in KM3-acute myeloid leukemia, and suggested the potential for autocrine signaling through the chemokine receptor CCR1 and CCL23 ligand. Collectively, our results sug- gest that KM3 induces subtle changes in the epigenome while co-opting the normal transcriptional machinery to drive leukemogenesis.
Introduction
Leukemias are a class of blood disorders characterized by the uncontrolled pro- liferation of hematopoietic stem and progenitor cells (HSPC) that have acquired a block in the normal process of differentiation.1-3 Recent large-scale studies have highlighted the age-related genetic differences between pediatric and adult acute myeloid leukemia (AML) and have also revealed the high level of genetic hetero- geneity in this disease.4 Not only are chromosomal translocations more frequent in younger patients, but recurrent mutations in specific genes implicated in the disease show a bias in either pediatric patients (e.g., NRAS, KIT, KRAS) or adults (DNMT3A, NPM1, IDH1/2).5 As a result, defining the combined role of these mutations in each patient, especially in pediatric patients in whom predisposition
Acute Myeloid Leukemia
Correspondence:
BRIAN T. WILHELM
brian.wilhelm@umontreal.ca
Received: September 7, 2020. Accepted: December 21, 2020. Pre-published: December 30, 2020.
https://doi.org/10.3324/haematol.2020.271619 ©2022 Ferrata Storti Foundation
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