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Blood. 2017 Mar 16;129(11):1491-1502. doi: 10.1182/blood-2016-06-721027. Epub 2017 Jan 4.

miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism.

Liu J1,2, Guo B1,2,3, Chen Z1,2,4, Wang N1,2,4, Iacovino M5, Cheng J1,2, Roden C1,2, Pan W1,2, Khan S6, Chen S7, Kyba M8, Fan R2,4, Guo S2,5, Lu J1,2,9.

Author information

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.
Department of Biomedical Engineering, Yale University, New Haven, CT.
Department of Cell Biology, and.
Department of Surgery, Yale University School of Medicine, New Haven, CT.
Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, MN; and.
Yale Center for RNA Science and Medicine, New Haven, CT.


The hematopoietic stem cell-enriched miR-125 family microRNAs (miRNAs) are critical regulators of hematopoiesis. Overexpression of miR-125a or miR-125b is 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 how miR-125 family miRNAs cooperate with known AML oncogenes in vivo, and how the resultant leukemia is dependent on miR-125 overexpression, are not well understood. We modeled the frequent co-occurrence of miR-125b overexpression and MLL translocations by examining functional cooperation between miR-125b and MLL-AF9 By generating a knock-in mouse model in which miR-125b overexpression is controlled by doxycycline induction, we demonstrated that miR-125b significantly enhances MLL-AF9-driven AML in vivo, and the resultant leukemia is partially dependent on continued overexpression of miR-125b Surprisingly, miR-125b promotes AML cell expansion and suppresses apoptosis involving a non-cell-intrinsic mechanism. MiR-125b expression enhances VEGFA expression and production from leukemia cells, in part by suppressing TET2 Recombinant VEGFA recapitulates the leukemia-promoting effects of miR-125b, whereas knockdown of VEGFA or inhibition of VEGF receptor 2 abolishes the effects of miR-125b In addition, significant correlation between miR-125b and VEGFA expression is observed in human AMLs. Our data reveal cooperative and dependent relationships between miR-125b and the MLL oncogene in AML leukemogenesis, and demonstrate a miR-125b-TET2-VEGFA pathway in mediating non-cell-intrinsic leukemia-promoting effects by an oncogenic miRNA.

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