DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia

Sara E. Meyer, Tingting Qin, David E. Muench, Kohei Masuda, Meenakshi Venkatasubramanian, Emily Orr, Lauren Suarez, Steven D. Gore, Ruud Delwel, Elisabeth M. Paietta, Martin S. Tallman, Hugo Fernandez, Ari Melnick, Michelle M. Le Beau, Scott Kogan, Nathan Salomonis, Maria E. Figueroa, H. Leighton Grimes

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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 (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3afloxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency.FLT3ITD/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 Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.

Original languageEnglish (US)
Pages (from-to)501-515
Number of pages15
JournalCancer Discovery
Volume6
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Oncology

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    Meyer, S. E., Qin, T., Muench, D. E., Masuda, K., Venkatasubramanian, M., Orr, E., Suarez, L., Gore, S. D., Delwel, R., Paietta, E. M., Tallman, M. S., Fernandez, H., Melnick, A., Le Beau, M. M., Kogan, S., Salomonis, N., Figueroa, M. E., & Grimes, H. L. (2016). DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia. Cancer Discovery, 6(5), 501-515. https://doi.org/10.1158/2159-8290.CD-16-0008