title: DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
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.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Meyer
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: David E
authors.initials: DE
authors.lastname: Muench
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kohei
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Venkatasubramanian
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Emily
authors.initials: E
authors.lastname: Orr
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lauren
authors.initials: L
authors.lastname: Suarez
authors.affiliation: Division of Hematologic Malignancies, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.affiliation: Department of Hematology, and Clinical Trial Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.affiliation: Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, Oncologic Sciences, College of Medicine at University of South Florida, Tampa, Florida.
authors.forename: Hugo
authors.initials: H
authors.lastname: Fernandez
authors.affiliation: Department of Medicine, Hematology/Oncology Division, Weill Cornell Medical College, New York, New York.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Section of Hematology/Oncology, and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Department of Laboratory Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: Scott
authors.initials: S
authors.lastname: Kogan
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Nathan
authors.initials: N
authors.lastname: Salomonis
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. lee.grimes@cchmc.org marfigue@med.umich.edu.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.affiliation: 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.
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
mesh_terms: D000818:Animals; D001706:Biopsy; D001853:Bone Marrow; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D005838:Genotype; D057895:Haploinsufficiency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology*; D019683:Penetrance; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051941:fms-Like Tyrosine Kinase 3