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PMID: 27016502 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Cancer discovery ·Vol. 6 ·No. 5 ·2016-00-00 ·Pages 501-15

Meyer SE, Qin T, Muench DE, Masuda K, Venkatasubramanian M, Orr E, Suarez L, Gore SD, Delwel R, Paietta E, Tallman MS, Fernandez H, Melnick A, Le Beau MM, Kogan S, Salomonis N, Figueroa ME, Grimes HL

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. 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.

MeSH Terms
Animals Biopsy Bone Marrow Cell Transformation, Neoplastic/genetics Cluster Analysis DNA (Cytosine-5-)-Methyltransferases/genetics DNA Methylation DNA Methyltransferase 3A Disease Models, Animal Disease Progression Gene Expression Profiling Gene Expression Regulation Genetic Loci Genotype Haploinsufficiency High-Throughput Nucleotide Sequencing Humans Karyotype Leukemia, Myeloid, Acute/etiology,mortality,pathology Mice Mice, Transgenic Mutation Myeloproliferative Disorders/genetics,pathology Penetrance Tandem Repeat Sequences fms-Like Tyrosine Kinase 3/genetics
Chemicals
DNMT3A protein, human Dnmt3a protein, mouse DNA (Cytosine-5-)-Methyltransferases DNA Methyltransferase 3A fms-Like Tyrosine Kinase 3
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Meyer Sara E
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Qin Tingting
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Muench David E
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Masuda Kohei
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Venkatasubramanian Meenakshi
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Orr Emily
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Suarez Lauren
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Gore Steven D
Division of Hematologic Malignancies, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
Delwel Ruud
Department of Hematology, and Clinical Trial Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
Paietta Elisabeth
Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
Tallman Martin S
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Fernandez Hugo
Blood and Marrow Transplantation, Moffitt Cancer Center, Oncologic Sciences, College of Medicine at University of South Florida, Tampa, Florida.
Melnick Ari
Department of Medicine, Hematology/Oncology Division, Weill Cornell Medical College, New York, New York.
Le Beau Michelle M
Section of Hematology/Oncology, and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois.
Kogan Scott
Department of Laboratory Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Salomonis Nathan
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Figueroa Maria E
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. [email protected] [email protected].
Grimes H Leighton
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. [email protected] [email protected].
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Article Info
Journal
Cancer discovery
Abbr.
Cancer Discov
ISSN
2159-8290
DOI
10.1158/2159-8290.CD-16-0008
Email
[email protected]
[email protected]
Published
2016-00-00
Epub
2016-00-25
Pages
501-15
Language
English
Region
United States
NLM ID
101561693
PMCID
PMC4861898
Subset
IM
Grants
NCI NIH HHS · R01 CA159845 · United States
NIEHS NIH HHS · T32 ES007250 · United States
NHLBI NIH HHS · U01 HL099997 · United States
NCI NIH HHS · U24 CA196172 · United States
NCI NIH HHS · R01 CA196658 · United States
NCATS NIH HHS · UL1 TR001425 · United States
NCI NIH HHS · U10 CA180820 · United States
NIGMS NIH HHS · T32 GM008752 · United States
NCI NIH HHS · R21 CA186945 · United States
NCI NIH HHS · P30 CA008748 · United States
External Links
PubMed source DOI: 10.1158/2159-8290.CD-16-0008 PMC Full Text View journal details
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