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

Jun Liu, Bo Guo, Zhuo Chen, Nayi Wang, Michelina Iacovino, Jijun Cheng, Christine Roden, Wen Pan, Sajid Khan, Suning Chen, Michael Kyba, Rong Fan, Shangqin Guo and Jun Lu

Key points

  • miR-125b overexpression accelerates MLL-AF9-driven AML, and endows partial addiction to its overexpression.

  • A miR-125b-TET2-VEGFA pathway promotes leukemogenesis involving a non-cell-intrinsic mechanism.

Abstract

The hematopoietic-stem-cell-enriched miR-125-family miRNAs are critical regulators of hematopoiesis. Overexpression of miR-125a or miR-125b are frequent in human acute myeloid leukemia (AML), and their overexpression 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 is 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 (Dox) induction, we demonstrate 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 miR-125b's leukemia-promoting effects, whereas knockdown of VEGFA or inhibition of VEGFR2 abolishes miR-125b's effects. 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 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.

  • Submitted June 8, 2016.
  • Accepted December 28, 2016.