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Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.

ABSTRACT: Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

SUBMITTER: Borkin D

PROVIDER: S-EPMC4415852 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.

Borkin Dmitry D He Shihan S Miao Hongzhi H Kempinska Katarzyna K Pollock Jonathan J Chase Jennifer J Purohit Trupta T Malik Bhavna B Zhao Ting T Wang Jingya J Wen Bo B Zong Hongliang H Jones Morgan M Danet-Desnoyers Gwenn G Guzman Monica L ML Talpaz Moshe M Bixby Dale L DL Sun Duxin D Hess Jay L JL Muntean Andrew G AG Maillard Ivan I Cierpicki Tomasz T Grembecka Jolanta J

Cancer cell 20150326 4

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mou ...[more]

PMID: 25817203

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Project description: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 level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-?B) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.

Dataset Information

Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.

Publications

Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.

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