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

Christiaan J Stavast1, Iris van Zuijen1, Elena Karkoulia2,3

  • 1Erasmus MC, University Medical Center Rotterdam, Department of Immunology, Rotterdam, the Netherlands.

Leukemia
|November 6, 2021
PubMed

Insights

MicroRNA-139 (MIR139) acts as a tumor suppressor in acute myeloid leukemia (AML). MLL-AF9 fusion protein silences MIR139 via epigenetic mechanisms involving PRC2 and POLR2M, offering potential therapeutic targets.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • MicroRNA-139 (MIR139) is a known tumor suppressor frequently silenced in acute myeloid leukemia (AML).
  • The precise functions of MIR139 and the mechanisms behind its silencing in AML remain poorly understood.
  • This study focuses on AML characterized by the MLL-AF9 fusion protein, a poor prognostic indicator.

Purpose of the Study:

  • To elucidate the molecular mechanisms of MIR139 silencing in MLL-AF9-driven AML.
  • To identify the functional targets of MIR139 that mediate its tumor-suppressive effects in AML.
  • To explore novel regulatory factors involved in MIR139 expression control.

Main Methods:

  • Investigated the effect of MLL-AF9 on MIR139 expression in hematopoietic precursors.
  • Assessed the impact of MIR139 overexpression on AML cell growth in vitro and in vivo.
  • Utilized CRISPR-Cas9 screening to identify MIR139 regulatory factors.
  • Analyzed the role of Polycomb Repressive Complex 2 (PRC2) in MIR139 epigenetic silencing.

Main Results:

  • MLL-AF9 expression leads to epigenetic silencing of MIR139 in hematopoietic precursors.
  • MIR139 overexpression effectively inhibits both in vitro and in vivo AML progression.
  • Two enhancer regions were identified as critical for controlling MIR139 expression.
  • PRC2, downstream of MLL-AF9, was confirmed to epigenetically silence MIR139.
  • A genome-wide CRISPR-Cas9 screen identified RNA Polymerase 2 Subunit M (POLR2M) as a novel factor regulating MIR139.

Conclusions:

  • MLL-AF9 orchestrates the epigenetic silencing of the tumor suppressor MIR139 in AML through PRC2 and POLR2M.
  • These findings reveal a novel mechanism of tumor suppressor regulation in AML.
  • The identified regulatory pathway presents potential new therapeutic strategies for AML treatment.

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