title: Loss of Dnmt3a and endogenous Kras(G12D/+) cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis.
abstract: Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/ CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a(-/-) induces multiple hematopoietic phenotypes after a prolonged latency, including T-cell expansion in the peripheral blood, stress erythropoiesis in the spleen and myeloid malignancies in the liver. Dnmt3a(-/-) significantly promoted JMML/CMML progression and shortened the survival of Kras(G12D/+) mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in Nras(G12D/+) mice. Further studies show that Dnmt3a deficiency rescues Kras(G12D/+)-mediated depletion of hematopoietic stem cells and increases self-renewal of Kras(G12D/+) myeloid progenitors (MPs). Moreover, ~33% of animals developed an AML-like disease, which is driven by Kras(G12D/+); Dnmt3a(-/-) MPs. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies.
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.|Institute of Physiology, National Yang-Ming University, Taipei City, Taiwan.
authors: Y-I
authors: YI
authors: Chang
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: X
authors: X
authors: You
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: G
authors: G
authors: Kong
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
authors: E A
authors: EA
authors: Ranheim
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: J
authors: J
authors: Wang
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: J
authors: J
authors: Du
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: Y
authors: Y
authors: Liu
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: Y
authors: Y
authors: Zhou
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.|Department of Medical Science, School of Medicine, Yonsei University, Seoul, Korea.
authors: M-J
authors: MJ
authors: Ryu
authors: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors: J
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D015536:Down-Regulation; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D019683:Penetrance; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D016283:Proto-Oncogene Proteins p21(ras)