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.

• MeSH
• akutní myeloidní leukemie genetika   MeSH
• epigeneze genetická MeSH
• fúzní onkogenní proteiny genetika   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protoonkogenní protein MLL genetika   MeSH
• regulace genové exprese u leukemie MeSH
• RNA-polymerasa II genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• mikro RNA MeSH
• MIRN139 microRNA, human MeSH Prohlížeč
• MIRN139 microRNA, mouse MeSH Prohlížeč
• MLL-AF9 fusion protein, human MeSH Prohlížeč
• POLR2M protein, human MeSH Prohlížeč
• Polr2m protein, mouse MeSH Prohlížeč
• protoonkogenní protein MLL MeSH
• RNA-polymerasa II MeSH