DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias.
DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Liubin
L
Yang
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Benjamin
B
Rodriguez
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Allison
A
Mayle
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Hyun Jung
HJ
Park
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Bioinformatics, School of Life sciences and Technology, Tongji University, Shanghai 20092, China.
Xueqiu
X
Lin
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Min
M
Luo
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Mira
M
Jeong
Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA.
Choladda V
CV
Curry
Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sang-Bae
SB
Kim
Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
David
D
Ruau
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Xiaotian
X
Zhang
Greehey Children's Cancer Research Institute and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Ting
T
Zhou
Rice University, Houston, Texas 77030, USA.
Michael
M
Zhou
Greehey Children's Cancer Research Institute and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Vivienne I
VI
Rebel
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Grant A
GA
Challen
Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
Berthold
B
Gottgens
Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ju-Seog
JS
Lee
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Rachel
R
Rau
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wei
W
Li
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Margaret A
MA
Goodell
D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3