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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00555495" target="_blank" >RIV/68378050:_____/22:00555495 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11130/22:10433649

Result on the web

<a href="https://www.nature.com/articles/s41375-021-01461-5" target="_blank" >https://www.nature.com/articles/s41375-021-01461-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41375-021-01461-5" target="_blank" >10.1038/s41375-021-01461-5</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30204 - Oncology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Leukemia

ISSN

0887-6924

e-ISSN

1476-5551

Volume of the periodical

36

Issue of the periodical within the volume

3

Country of publishing house

GB - UNITED KINGDOM

Number of pages

14

Pages from-to

687-700

UT code for WoS article

000714877400003

EID of the result in the Scopus database

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