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The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis
CJ. Stavast, I. van Zuijen, E. Karkoulia, A. Özçelik, A. van Hoven-Beijen, LG. Leon, JSA. Voerman, GMC. Janssen, PA. van Veelen, M. Burocziova, RWW. Brouwer, WFJ. van IJcken, A. Maas, EM. Bindels, VHJ. van der Velden, C. Schliehe, PD. Katsikis,...
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1997-01-01
Nursing & Allied Health Database (ProQuest)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Leukemia, Myeloid, Acute genetics MeSH
- Epigenesis, Genetic MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Carcinogenesis genetics MeSH
- Humans MeSH
- MicroRNAs genetics MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Cell Line, Tumor MeSH
- Myeloid-Lymphoid Leukemia Protein genetics MeSH
- Gene Expression Regulation, Leukemic MeSH
- RNA Polymerase II genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Center for Proteomics and Metabolomics Leiden University Medical Center Leiden the Netherlands
Erasmus MC University Medical Center Rotterdam Center for Biomics Rotterdam the Netherlands
Erasmus MC University Medical Center Rotterdam Department of Cell Biology Rotterdam the Netherlands
Erasmus MC University Medical Center Rotterdam Department of Hematology Rotterdam the Netherlands
Erasmus MC University Medical Center Rotterdam Department of Immunology Rotterdam the Netherlands
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