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bioRxiv · 10.1101/2022.05.17.492246

Menin-MLL Inhibitor MI-503 Blocks Menin Nuclear Export and Suppresses Hypergastrinemia

Merchant, J. L.·Wang, Z.·Sundaresan, S.
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Abstract

Menin is the protein product of the Multiple Endocrine Neoplasia 1 (MEN1) gene locus at 11q13 and is a known tumor suppressor of neuroendocrine neoplasms (NENs). Gastrin-expressing NENs (gastrinomas) comprise the most frequent and malignant of the MEN1-dependent endocrine tumors. When gastrinomas are part of the MEN1 syndrome, they exhibit a greater propensity to develop within the submucosal Brunners glands of the duodenum. Therefore, models to analyze the biology of these intestinal gastrin-expressing NENs should consider their submucosal location. AimThe goal of this study was to determine whether the Menin-MLL inhibitor MI-503 suppressed hypergastrinemia. MethodsA murine model of hypergastrinemia generated by omeprazole treatment of mice carrying a conditional deletion of Men1 bred onto a somatostatin null genetic background (OMS) was treated intraperitoneally with MI-503 for 1 month. Primary enteric glial cells were prepared from these OMS mice and were treated with increasing doses of MI-503. Similarly human AGS and mouse STC-1 gastrin producing cell lines were treated with EGF without or with MI-503. >ResultsWe found that the treatment reduced serum and gastro-duodenal tissue expression of gastrin. Ex vivo MI-503 treatment of glial fibrillary acidic protein (GFAP)+ enteric cells isolated from the OMS mice or gastrin-expressing cell lines revealed that MI-503 blocked the nuclear export of Menin and suppressed gastrin gene expression. RNA-Seq analysis of gastrin-treated GFAP+ enteric cells revealed that they express EGF receptor ligands and that EGF treatment of GFAP+ cells also induced Menin translocation and concurrent induction of gastrin gene expression. ConclusionWe concluded that MI-503 inhibits gastrin gene expression by blocking Menin translocation.

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Merchant, J. L., Wang, Z., Sundaresan, S.. 2022-05-18. Menin-MLL Inhibitor MI-503 Blocks Menin Nuclear Export and Suppresses Hypergastrinemia. https://doi.org/10.1101/2022.05.17.492246

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