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Endocrine Abstracts (2014) 34 S9.1 | DOI: 10.1530/endoabs.34.S9.1

SFEBES2014 Symposia MEN1 ‐ from molecular pathology to therapies (Supported by <emphasis role="italic">Endocrine-Related Cancer</emphasis>) (3 abstracts)

Current understanding and future perspectives in MEN1: the molecular pathology of the MEN1 gene and menin

Sunita Agarwal


National Institutes of Health, Bethesda, Maryland, USA.


The MEN1 gene is located on chromosome 11q13; it spans 9 kb, has ten exons, and encodes a 610 amino acid protein named menin (isoform-2, NCBI Reference Sequence: NP_570711.1). Germline heterozygous inactivating mutations in this gene are observed in 70% of patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome who develop multiple tumours in various endocrine (parathyroid, pancreas, and pituitary) and non-endocrine tissues with loss of the remaining normal MEN1 allele. Also, a variety of MEN1-like non-familial sporadic tumours possess somatic biallelic inactivation/loss of MEN1. With more than 1000 MEN1 mutations reported, significant hot spots and genotype–phenotype correlations are not obvious. Identification of this gene has facilitated genetic testing for germline MEN1 mutations in at-risk individuals that allows early monitoring for tumours. Further investigations are required to elucidate the genetic causes of MEN1 in patients (30%) who lack an identifiable germline MEN1 mutation. Menin is ubiquitously expressed and predominantly nuclear. Majority of the protein-truncating MEN1 mutations disrupt the nuclear localization signals predicting functional consequences due to defective localization of menin. Thirty percent of MEN1 mutations are missense. The recently deciphered crystal structure of menin can help to determine their consequence. Menin can undergo phosphorylation at Ser394, Thr397, Thr399, Ser487, Ser543, and Ser583. The importance of phosphorylated menin in normal and tumour cells should be further investigated. Mouse models, protein interaction studies, and gene expression analyses have been used to explore the critical biological function/s of menin. Men1−/− mice are embryonic lethal (E10.5–14.5), while the Men1+/− mice re-capitulate the human MEN1 syndrome. Menin is required in the MLL-complex for the epigenetic H3K4me3 chromatin modification. Anti-H3K4me3 ChIP-Seq in WT and Men1−/− mouse embryonic stem cells, and in in vitro differentiated pancreatic islet-like endocrine cells revealed menin-dependent expression of genes at the Meg3 locus and at the four Hox loci. Interestingly, in MLL-fusion leukaemia menin-dependent expression of Hox genes is essential for the action of oncogenic MLL-fusions. Exploring this tumour-suppressing vs pro-oncogenic function of menin is of interest to identify druggable targets in MEN1-associated and similar sporadic tumours, and in MLL-fusion leukaemia. Thus, studies about the MEN1 gene and menin can improve the management of MEN1-associated and sporadic tumours, and can help to develop new diagnostic and therapeutic options.

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