The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis

Leukemia. 2022 Mar;36(3):687-700. doi: 10.1038/s41375-021-01461-5. Epub 2021 Nov 5.


MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Oncogene Proteins, Fusion / genetics
  • RNA Polymerase II / genetics*


  • MIRN139 microRNA, human
  • MIRN139 microRNA, mouse
  • MLL-AF9 fusion protein, human
  • MicroRNAs
  • Oncogene Proteins, Fusion
  • POLR2M protein, human
  • Polr2m protein, mouse
  • Myeloid-Lymphoid Leukemia Protein
  • RNA Polymerase II