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Cancer Discov. 2016 May;6(5):501-15. doi: 10.1158/2159-8290.CD-16-0008. Epub 2016 Mar 25.

DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.

Author information

1
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
2
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
3
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
4
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Division of Hematologic Malignancies, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
6
Department of Hematology, and Clinical Trial Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
7
Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
8
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Blood and Marrow Transplantation, Moffitt Cancer Center, Oncologic Sciences, College of Medicine at University of South Florida, Tampa, Florida.
10
Department of Medicine, Hematology/Oncology Division, Weill Cornell Medical College, New York, New York.
11
Section of Hematology/Oncology, and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois.
12
Department of Laboratory Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
13
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. lee.grimes@cchmc.org marfigue@med.umich.edu.
14
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. lee.grimes@cchmc.org marfigue@med.umich.edu.

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 (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.

PMID:
27016502
PMCID:
PMC4861898
DOI:
10.1158/2159-8290.CD-16-0008
[Indexed for MEDLINE]
Free PMC Article

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