Abstract 3652: EED or BRD4 inhibition as a novel therapeutic strategy in acute myeloid leukemia with monosomy 7
Authors: Kensuke Matsuda, Yuki Kagoya, Hideaki Mizuno, Sho Yamazaki, Masashi Miyauchi, Mineo Kurokawa
Journal: Cancer Research (2020)

Abstract Backgrounds: Monosomy of chromosome 7 (monosomy 7) is observed in about 9% of acute myeloid leukemia (AML) patients and related to poor prognosis. It is required to establish an effective treatment strategy based on the specific molecular pathogenesis associated with the chromosomal abnormality. Methods: Chromosome 7 encodes multiple genes regulating histone methylation. We hypothesized that haploinsufficiency of the epigenetic modifiers in the chromosome 7 is compensated by other epigenetic molecules in different chromosomes, and the AML cells with monosomy 7 are vulnerable to inhibition of those molecules. Based on this notion, we performed an RNA-interference (RNAi)-based screening by targeting 53 genes encoding epigenetic enzymes regulating histone methylation by using AML cell lines with monosomy 7 and non-monosomy 7. Results: We found that the siRNA-mediated knockdown of EED, or BRD4 significantly decreased cell viability in AML cells with monosomy 7 compared to the control leukemia cell lines. Stable knockdown of EED markedly attenuated proliferation as well as increased cell apoptosis specifically in leukemia cells with monosomy 7. Interestingly, PRC1 rather than PRC2 activity of EED had a predominant role in the survival of monosomy 7 leukemia cells. We then explored whether the deletion of specific genes within the chromosome 7 was responsible for increased sensitivity to EED inhibition. We found that knockdown of GTF2I increased the sensitivity to EED inhibition via increased cell apoptosis. Because both GTF2I and EED suppressed expression levels of BCL2, it is possible that EED inhibition additively abrogate BCL2 activity in AML with monosomy 7. In addition to EED, we identified BRD4 as another essential survival factor in AML with monosomy 7. Although inhibition of BET bromodomain proteins have already shown to be effective for a variety of AML, we showed that blockade of bromodomain proteins preferentially affected cellular proliferation of AML cells with monosomy 7. Mechanistically, we found that knockout of MLL3 or MLL5, both encoded in the chromosome 7, resulted in increased vulnerability to JQ-1 treatment. In monosomy 7, functional loss of MLL3 and MLL5 showed reduced expression levels of c-MYC and CCND1. JQ-1 treatment additively impaired the functions of these genes, and strongly inhibited cell proliferation of AML cells with monosomy 7. Conclusion: Our synthetic-lethality based approach identified EED and BRD4 as novel promising therapeutic targets in AML with monosomy 7. Citation Format: Kensuke Matsuda, Yuki Kagoya, Hideaki Mizuno, Sho Yamazaki, Masashi Miyauchi, Mineo Kurokawa. EED or BRD4 inhibition as a novel therapeutic strategy in acute myeloid leukemia with monosomy 7 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3652.