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
• 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
• Mice 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
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• MicroRNAs MeSH
• MIRN139 microRNA, human MeSH Browser
• MIRN139 microRNA, mouse MeSH Browser
• MLL-AF9 fusion protein, human MeSH Browser
• POLR2M protein, human MeSH Browser
• Polr2m protein, mouse MeSH Browser
• Myeloid-Lymphoid Leukemia Protein MeSH
• RNA Polymerase II MeSH