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

0555495 - ÚMG 2023 RIV GB eng J - Journal Article
Stavast, C. - van Zuijen, I. - Karkoulia, Eleni - Ozcelik, A. - Van Hoven-Beijen, A. - Leon, L. - Voerman, J.S.A. - Janssen, G. - van Veelen, P. - Burocziová, Monika - Brouwer, R. - van Ijcken, W. - Maas, A. - Bindels, E.M. - van der Velden, V. - Schliehe, C. - Katsikis, P.D. - Alberich-Jorda, Meritxell - Erkeland, S.
The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis.
Leukemia. Roč. 36, č. 3 (2022), s. 687-700. ISSN 0887-6924. E-ISSN 1476-5551
Institutional support: RVO:68378050
Keywords : epithelial-mesenchymal transition * prc2 recruitment * myeloid-leukemia * inhibition * apoptosis * expression * chromatin * micrornas * enhancer * protein
OECD category: Oncology
Impact factor: 11.4, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s41375-021-01461-5

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.
Permanent Link: http://hdl.handle.net/11104/0330002