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.
Bibliographical noteFunding Information: For this work, C.J.S. and I.V.Z. were supported by the Dutch Cancer Foundation (KWF), grant no.: 10948. Furthermore, the Dutch Research Council (NWO) Medium Investment Grant 91116004 (partly financed by ZonMw) to P.A.v.V. also supported the work. Furthermore, we would like to thank Yvette Caljouw, Fabiënne van Opstal, Bernard Stikker and Stijn van den Broek for their technical assistance and Dr. G. Dal Collo and Dr. C. Kiernan for critically reviewing the manuscript. In addition, we would like to acknowledge Dr. R. Delwel and Dr. R. Avelino for their experimental and technical advice.
Publisher Copyright: © 2021, The Author(s).