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About the Authors:
Sunita K. Agarwal
* E-mail: [email protected] (SKA); [email protected] (RJ)
Affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Raja Jothi
* E-mail: [email protected] (SKA); [email protected] (RJ)
Affiliation: Systems Biology Section, Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
Introduction
Whole exome sequencing of different tumor types has identified mutations in various genes whose products are associated with epigenetic processes that are involved in chromatin modification [1]. Sporadic pancreatic endocrine/neuroendocrine tumors of the hormone secreting islet cells of the pancreas harbor inactivating mutations in MEN1 encoding menin, a component of histone methyltransferase complexes, in 27–44% of tumors [2], [3]. Also, 14–25% of these tumors have mutations in DAXX or ATRX that encode subunits of a chromatin-remodeling complex [3]. Menin is found in a subset of COMPASS-like (complex of proteins associated with Set1) mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), specifically in MLL1/MLL2-containing complexes that trimethylate H3K4 [4], [5]. The MLL core complex consists of homologs of proteins found in the yeast Set1 histone methyltransferase (HMT) complex such as ASH2, RBBP5, and WDR5.
Menin acts as a tumor suppressor in the autosomal dominant multiple endocrine neoplasia type 1 (MEN1) syndrome characterized by tumors of hormone producing cells of the parathyroids, enteropancreatic endocrine tissues, and anterior pituitary [6]. Menin is essential for early development as indicated by the embryonic lethality at E11.5-E13.5 of homozygous Men1-knockout (Men1-ko) mouse embryos [7]. Men1 loss in mouse models driven by RIP-Cre, GLU-Cre, or PDX1-Cre show islet endocrine cell-type restricted tumorigenesis, implicating an essential role for menin in islet endocrine cell homeostasis [7], [8], [9], [10].
Surprisingly, menin's association with MLL is pro-oncogenic in MLL-associated leukemia cells. About 50–60 different translocations involving the MLL1 gene are known to cause acute lymphoid and myeloid leukemias with increased expression of specific homeobox (HOX) genes such as HOXA7, HOXA9, and the HOX cofactor MEIS1 [11]. Menin binds to the highly conserved N-terminal 44 amino acids of MLL1 or MLL2; hence, N-terminal MLL peptides could serve as dominant negative inhibitors of the MLL-menin interaction, inhibiting the growth of MLL-transformed leukemic cells...