DNMT3A Haploinsufficiency Transforms FLT3 ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia
Year: 2016
Type: article
Abstract: UNLABELLED: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. SIGNIFICANCE: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
Source: Cancer Discovery
Authors: Sara E. Meyer, Tingting Qin, David E. Muench, Kohei Masuda, Meenakshi Venkatasubramanian, Emily Orr, Lauren Suarez, Steven D. Gore, Ruud Delwel, Elisabeth Paietta, Martin S. Tallman, Hugo Fernandez, Ari Melnick, Michelle M. Le Beau, Scott Kogan, Nathan Salomonis, Maria E. Figueroa, H. Leighton Grimes
Institutions: Cincinnati Children's Hospital Medical Center, University of Michigan, Michigan Medicine, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Yale Cancer Center, Yale University, Erasmus MC, Albert Einstein College of Medicine, Montefiore Medical Center, Memorial Sloan Kettering Cancer Center, University of South Florida, Moffitt Cancer Center, Weill Cornell Medicine, University of Chicago, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Leukemia and Lymphoma Society, Cincinnati Children's Hospital Medical Center, University of Cincinnati, CancerFree KIDS, National Institutes of Health, Erasmus Universitair Medisch Centrum Rotterdam, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences
Awards: ECOG-ACRIN Network Group Operations Center, Progenitor Cell Biology Consortium Administrative Coordinating Center, Environmental Carcinogenesis and Mutagenesis, A rapid spontaneous murine model of CN-AML, Center for Clinical and Translational Science and Training, Developing Novel STAT5 Protein Inhibitors for treatment of leukemias, MicroRNA in Acute Myeloid Leukemia, Cellular and Molecular Medicine, Cancer Center Support Grant, ECOG-ACRIN Biospecimen Bank to Support NCTN
OpenAlex ID: W2308905752