Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

Clinical Epigenetics
Jing YeBing Xu

Abstract

While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the ...Continue Reading

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Citations

Dec 8, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shujing ZhangHongmin Liu
Feb 4, 2021·ChemMedChem·Ezgi Ozyerli-GoknarH T Marc Timmers
Jun 14, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Nok-Hei Mickey Wong, Chi Wai Eric So
Jun 9, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yi WangBo Liu
Jul 25, 2021·International Journal of Molecular Sciences·Alvina I KhamidullinaAlexandra V Bruter

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Methods Mentioned

BETA
xenograft
flow cytometry
flow
Assay
RNAseq
PCR
acetylation
FACS

Software Mentioned

GSEA
CompuSyn
GESA
GraphPad Prism
SPSS

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