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Am J Cancer Res. 2019 Aug 1;9(8):1682-1694. eCollection 2019.

Disruption of the menin-MLL interaction triggers menin protein degradation via ubiquitin-proteasome pathway.

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Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University Wuhan 430071, China.
Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 19014, PA, USA.
Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430071, China.
Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 19014, PA, USA.


Menin, a protein encoded by the MEN1 gene, suppresses cancers associated with multiple endocrine neoplasia type 1 (MEN1), but promotes the development of a subset of leukemia induced by mixed lineage leukemia (MLL)-derived fusion proteins (MLL-FPs). The crystal structure of menin indicates that it acts as a scaffold protein to bind the N-terminus of MLL via a central pocket. Small molecule menin-MLL inhibitors (MIs) bind the menin pocket to disrupt the menin/MLL interaction, resulting in suppression of MLL-FP-transformed acute myeoloid leukemia (AML). It is thought that MIs suppress the MLL-FP-induced leukemia by blocking the menin/MLL interaction and menin/MLL-induced HOX gene transcription. However, it is not clear whether MIs also affect other aspects of menin biology beyond disruption of the menin/MLL interaction. Here we show for the first time that MIs reduced menin protein levels and decreased the half-life of menin protein but have no effect on mRNA level in MLL-FP-expressing leukemia cells, and proteasome or E1 ligase inhibitor rescued the MI-induced menin degradation. Notably, the MI-induced reduction of H3K4m3 and HOXA9 expression was rescued with a proteasome inhibitor that blocks MI-induced menin protein degradation. Mechanistically, MIs promote the interaction of menin with Hsp70-associated ubiquitin ligase CHIP, resulting in increased menin ubiquitination, leading to increased menin degradation. Together, these findings uncover a novel mechanism whereby small molecule MIs increase menin degradation by triggering the Hsp70/CHIP-mediated ubiquitin-proteasome pathway that ultimately leads to the reduction in HOXA9 gene expression and leukemia suppression.


Menin; leukemia; menin-MLL inhibitor; ubiquitin-proteasome pathway


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