title: Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells.
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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Guryanova
authors.affiliation: Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
authors.forename: Y K
authors.initials: YK
authors.lastname: Lieu
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: 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.
authors.forename: J L
authors.initials: JL
authors.lastname: Glass
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shank
authors.affiliation: Hematology Unit, University of Florence, Florence, Italy.
authors.forename: A B V
authors.initials: AB
authors.lastname: Martinez
authors.affiliation: Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Rivera
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Durham
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bastian
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tovbin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Weinstein
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: 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.
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Hematology Unit, University of Florence, Florence, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Santini
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: 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.
authors.forename: R L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002465:Cell Movement; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008099:Liver / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A