Abstract
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.
Highlights
Mixed-lineage leukemia (MLL) or Lysine Methyltransferase 2A (KMT2A) rearrangements occur in 10% of adult acute leukemias and in 35% of pediatric cases [1, 2]
We show that MIR139 is a critical tumor suppressor activity, offering potential targets of intervention for suppressor that is silenced by MLL-AF9 in acute myeloid leukemia (AML)
In concordance with previous studies [22, 29], we found enrichment of PRC1 and polycomb repressive complex 2 (PRC2) targets, class-I (EZH2-controlled) and class-II (EZH2-independent) PcG target genes in the set of downregulated genes in MLL-AF9 cells compared to WT HSPCs (Supplementary Fig. 1F)
Summary
Mixed-lineage leukemia (MLL) or Lysine Methyltransferase 2A (KMT2A) rearrangements occur in 10% of adult acute leukemias and in 35% of pediatric cases [1, 2]. MLL rearrangements cause inframe fusions with >60 different genes of which AF4, AF9, AF10, ENL, and ELL are most common [3, 4]. MLL-fusion proteins cause heterogeneous leukemia of lymphoid or myeloid origin and are associated with therapy resistance and poor prognosis [3, 5]. MLLfusion proteins retain the DNA-binding domain of MLL and deregulate target genes that are normally controlled by MLL [6]. The most common MLL-rearrangement in acute myeloid leukemia (AML) is caused by the t(9;11)(p22q23) fusing MLL to the AF9 gene in-frame and occurs in 30% of MLL-rearranged AMLs [3, 5]. Continuous expression of MLL-AF9 is critical for the survival of AML cells, which suggests that genes deregulated by MLL-AF9 are potential targets for therapy [7, 8]
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