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PMID: 26710888 Published · ppublish English Journal Article

Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells.

Leukemia ·Vol. 30 ·No. 5 ·2016-00-00 ·Pages 1133-42

Guryanova OA, Lieu YK, Garrett-Bakelman FE, Spitzer B, Glass JL, Shank K, Martinez AB, Rivera SA, Durham BH, Rapaport F, Keller MD, Pandey S, Bastian L, Tovbin D, Weinstein AR, Teruya-Feldstein J, Abdel-Wahab O, Santini V, Mason CE, Melnick AM, Mukherjee S, Levine RL

Abstract

DNA methyltransferase 3A (DNMT3A) mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here, we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant MPN with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell-autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.

MeSH Terms
Animals Bone Marrow Cells Cell Movement Cell Proliferation Cell Self Renewal DNA (Cytosine-5-)-Methyltransferases/physiology DNA Methyltransferase 3A Hematopoiesis Hematopoietic Stem Cells/cytology Liver/pathology Mice Myeloid Cells/cytology
Chemicals
DNMT3A protein, human Dnmt3a protein, mouse DNA (Cytosine-5-)-Methyltransferases DNA Methyltransferase 3A
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Guryanova O A
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lieu Y K
Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
Garrett-Bakelman F E
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Spitzer B
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Glass J L
Department of Medicine, Weill Cornell Medical College, New York, NY, USA. | Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Shank K
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Martinez A B V
Hematology Unit, University of Florence, Florence, Italy.
Rivera S A
Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
Durham B H
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Rapaport F
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Keller M D
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Pandey S
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Bastian L
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Tovbin D
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weinstein A R
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Teruya-Feldstein J
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abdel-Wahab O
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. | Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Santini V
Hematology Unit, University of Florence, Florence, Italy.
Mason C E
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
Melnick A M
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Mukherjee S
Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
Levine R L
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. | Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. | Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Article Info
Journal
Leukemia
Abbr.
Leukemia
ISSN
1476-5551
DOI
10.1038/leu.2015.358
Published
2016-00-00
Epub
2015-00-29
Pages
1133-42
Language
English
Region
England
NLM ID
8704895
PMCID
PMC4856586
Subset
IM
Grants
NCI NIH HHS · R25 CA020449 · United States
NCI NIH HHS · T32 CA009207 · United States
NCI NIH HHS · U24 CA196172 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · R01 CA169784 · United States
NCI NIH HHS · U10 CA180820 · United States
NCI NIH HHS · K99 CA178191 · United States
NCI NIH HHS · U10 CA180827 · United States
NCI NIH HHS · R01 CA173636 · United States
NCI NIH HHS · K08 CA169055 · United States
External Links
PubMed source DOI: 10.1038/leu.2015.358 PMC Full Text View journal details
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