title: miR-125bpromotesMLL-AF9-driven murine acute myeloid leukemia involving aVEGFA-mediated non-cell-intrinsic mechanism.
abstract: The hematopoietic stem cell-enrichedmiR-125family microRNAs (miRNAs) are critical regulators of hematopoiesis. Overexpression ofmiR-125aormiR-125bis frequent in human acute myeloid leukemia (AML), and the overexpression of these miRNAs in mice leads to expansion of hematopoietic stem cells accompanied by perturbed hematopoiesis with mostly myeloproliferative phenotypes. However, whether and howmiR-125family miRNAs cooperate with known AML oncogenes in vivo, and how the resultant leukemia is dependent onmiR-125overexpression, are not well understood. We modeled the frequent co-occurrence ofmiR-125boverexpression andMLLtranslocations by examining functional cooperation betweenmiR-125bandMLL-AF9By generating a knock-in mouse model in whichmiR-125boverexpression is controlled by doxycycline induction, we demonstrated thatmiR-125bsignificantly enhancesMLL-AF9-driven AML in vivo, and the resultant leukemia is partially dependent on continued overexpression ofmiR-125bSurprisingly,miR-125bpromotes AML cell expansion and suppresses apoptosis involving a non-cell-intrinsic mechanism.MiR-125bexpression enhancesVEGFAexpression and production from leukemia cells, in part by suppressingTET2Recombinant VEGFA recapitulates the leukemia-promoting effects ofmiR-125b, whereas knockdown ofVEGFAor inhibition of VEGF receptor 2 abolishes the effects ofmiR-125bIn addition, significant correlation betweenmiR-125bandVEGFAexpression is observed in human AMLs. Our data reveal cooperative and dependent relationships betweenmiR-125band theMLLoncogene in AML leukemogenesis, and demonstrate amiR-125b-TET2-VEGFApathway in mediating non-cell-intrinsic leukemia-promoting effects by an oncogenic miRNA.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: Nayi
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, and.
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.
authors.forename: Christine
authors.initials: C
authors.lastname: Roden
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.
authors.forename: Wen
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT.
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, MN; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.affiliation: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Department of Cell Biology, and.
authors.forename: Shangqin
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Stem Cell Center, Yale Cancer Center, New Haven, CT.|Yale Center for RNA Science and Medicine, New Haven, CT.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: C551356:MLL-AF9 fusion protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D015514:Oncogene Proteins, Fusion; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051788:Myeloid-Lymphoid Leukemia Protein