| Structural highlights
Disease
[MEN1_HUMAN] Defects in MEN1 are the cause of familial multiple endocrine neoplasia type I (MEN1) [MIM:131100]. Autosomal dominant disorder characterized by tumors of the parathyroid glands, gastro-intestinal endocrine tissue, the anterior pituitary and other tissues. Cutaneous lesions and nervous-tissue tumors can exist. Prognosis in MEN1 patients is related to hormonal hypersecretion by tumors, such as hypergastrinemia causing severe peptic ulcer disease (Zollinger-Ellison syndrome, ZES), primary hyperparathyroidism, and acute forms of hyperinsulinemia.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] Defects in MEN1 are the cause of familial isolated hyperparathyroidism (FIHP) [MIM:145000]; also known as hyperparathyroidism type 1 (HRPT1). FIHP is an autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid tumors.[41] [42] [43] [44] [45] [46] [47]
Function
[MEN1_HUMAN] Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair.[48] [49] [50] [51] [52]
Publication Abstract from PubMed
The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the Nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates for the first time profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1-rearrangements or NPM1 mutations.
Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.,Klossowski S, Miao H, Kempinska K, Wu T, Purohit T, Kim E, Linhares BM, Chen D, Jih G, Perkey E, Huang H, He M, Wen B, Wang Y, Yu K, Lee SC, Danet-Desnoyers G, Trotman W, Kandarpa M, Cotton A, Abdel-Wahab O, Lei H, Dou Y, Guzman M, Peterson L, Gruber TA, Choi SM, Sun D, Ren P, Li LS, Liu Y, Burrows FJ, Maillard I, Cierpicki T, Grembecka J J Clin Invest. 2019 Dec 19. pii: 129126. doi: 10.1172/JCI129126. PMID:31855575[53]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Agarwal SK, Debelenko LV, Kester MB, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Heppner C, Crabtree JS, Lubensky IA, Zhuang Z, Kim YS, Chandrasekharappa SC, Collins FS, Liotta LA, Spiegel AM, Burns AL, Emmert-Buck MR, Marx SJ. Analysis of recurrent germline mutations in the MEN1 gene encountered in apparently unrelated families. Hum Mutat. 1998;12(2):75-82. PMID:9671267 doi:<75::AID-HUMU1>3.0.CO;2-T 10.1002/(SICI)1098-1004(1998)12:2<75::AID-HUMU1>3.0.CO;2-T
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- ↑ Mayr B, Brabant G, von zur Muhlen A. Menin mutations in MEN1 patients. J Clin Endocrinol Metab. 1998 Aug;83(8):3004-5. PMID:9709985
- ↑ Boni R, Vortmeyer AO, Pack S, Park WS, Burg G, Hofbauer G, Darling T, Liotta L, Zhuang Z. Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. J Invest Dermatol. 1998 Sep;111(3):539-40. PMID:9740255 doi:10.1046/j.1523-1747.1998.00317.x
- ↑ Sakurai A, Shirahama S, Fujimori M, Katai M, Itakura Y, Kobayashi S, Amano J, Fukushima Y, Hashizume K. Novel MEN1 gene mutations in familial multiple endocrine neoplasia type 1. J Hum Genet. 1998;43(3):199-201. PMID:9747036 doi:10.1007/s100380050070
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- ↑ Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A. Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat. 1999;13(1):54-60. PMID:9888389 doi:<54::AID-HUMU6>3.0.CO;2-K 10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K
- ↑ Mutch MG, Dilley WG, Sanjurjo F, DeBenedetti MK, Doherty GM, Wells SA Jr, Goodfellow PJ, Lairmore TC. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13(3):175-85. PMID:10090472 doi:<175::AID-HUMU1>3.0.CO;2-R 10.1002/(SICI)1098-1004(1999)13:3<175::AID-HUMU1>3.0.CO;2-R
- ↑ Engelbach M, Forst T, Hankeln T, Tratzky M, Heerdt S, Pfutzner A, Kann P, Kunt T, Schneider S, Schmidt ER, Beyer J. Germline mutations in the MEN1 gene: creation of a new splice acceptor site and insertion of 7 intron nucleotides into the mRNA. Int J Mol Med. 1999 Nov;4(5):483-5. PMID:10534569
- ↑ Bergman L, Teh B, Cardinal J, Palmer J, Walters M, Shepherd J, Cameron D, Hayward N. Identification of MEN1 gene mutations in families with MEN 1 and related disorders. Br J Cancer. 2000 Oct;83(8):1009-14. PMID:10993647 doi:10.1054/bjoc.2000.1380
- ↑ Roijers JF, de Wit MJ, van der Luijt RB, Ploos van Amstel HK, Hoppener JW, Lips CJ. Criteria for mutation analysis in MEN 1-suspected patients: MEN 1 case-finding. Eur J Clin Invest. 2000 Jun;30(6):487-92. PMID:10849016
- ↑ Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E, Brandi ML. MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1. Eur J Endocrinol. 2000 Feb;142(2):131-7. PMID:10664520
- ↑ Weinhaeusel A, Vierhapper H, Schlegl R, Wagner T, Muhr D, Scheuba C, Niederle B, Haas OA. A novel mutation E179K of the MEN1 gene predisposes for multiple endocrine neoplasia-type 1 (MEN1). Hum Mutat. 2000 Dec;16(6):533. PMID:11102994 doi:<533::AID-HUMU22>3.0.CO;2-5 10.1002/1098-1004(200012)16:6<533::AID-HUMU22>3.0.CO;2-5
- ↑ Stratakis CA, Schussheim DH, Freedman SM, Keil MF, Pack SD, Agarwal SK, Skarulis MC, Weil RJ, Lubensky IA, Zhuang Z, Oldfield EH, Marx SJ. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2000 Dec;85(12):4776-80. PMID:11134142
- ↑ Asteria C, Faglia G, Roncoroni R, Borretta G, Ribotto P, Beck-Peccoz P. Identification of three novel menin mutations (c.741delGTCA, c.1348T>C, c.1785delA) in unrelated Italian families affected with multiple endocrine neoplasia type 1: Additional information for mutational screening. Hum Mutat. 2001 Mar;17(3):237. PMID:11241849 doi:10.1002/humu.12
- ↑ Wautot V, Vercherat C, Lespinasse J, Chambe B, Lenoir GM, Zhang CX, Porchet N, Cordier M, Beroud C, Calender A. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002 Jul;20(1):35-47. PMID:12112656 doi:10.1002/humu.10092
- ↑ Okamoto H, Tamada A, Hai N, Doi M, Uchimura I, Hirata Y, Kosugi S. A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism. Jpn J Clin Oncol. 2002 Sep;32(9):368-70. PMID:12417605
- ↑ Turner JJ, Leotlela PD, Pannett AA, Forbes SA, Bassett JH, Harding B, Christie PT, Bowen-Jones D, Ellard S, Hattersley A, Jackson CE, Pope R, Quarrell OW, Trembath R, Thakker RV. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2002 Jun;87(6):2688-93. PMID:12050235
- ↑ Pannett AA, Kennedy AM, Turner JJ, Forbes SA, Cavaco BM, Bassett JH, Cianferotti L, Harding B, Shine B, Flinter F, Maidment CG, Trembath R, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf). 2003 May;58(5):639-46. PMID:12699448
- ↑ Park JH, Kim IJ, Kang HC, Lee SH, Shin Y, Kim KH, Lim SB, Kang SB, Lee K, Kim SY, Lee MS, Lee MK, Park JH, Moon SD, Park JG. Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders. Clin Genet. 2003 Jul;64(1):48-53. PMID:12791038
- ↑ Crepin M, Escande F, Pigny P, Buisine MP, Calender A, Porchet N, Odou MF. Efficient mutation detection in MEN1 gene using a combination of single-strand conformation polymorphism (MDGA) and heteroduplex analysis. Electrophoresis. 2003 Jan;24(1-2):26-33. PMID:12652570 doi:10.1002/elps.200390023
- ↑ Ukita C, Yamaguchi M, Tanaka T, Shigeta H, Nishikawa M. A novel missense mutation of the MEN1 gene in a multiple endocrine neoplasia type 1 patient associated with carcinoid syndrome. Intern Med. 2003 Nov;42(11):1112-6. PMID:14686752
- ↑ Cebrian A, Ruiz-Llorente S, Cascon A, Pollan M, Diez JJ, Pico A, Telleria D, Benitez J, Robledo M. Mutational and gross deletion study of the MEN1 gene and correlation with clinical features in Spanish patients. J Med Genet. 2003 May;40(5):e72. PMID:12746426
- ↑ Jap TS, Chiu CY, Won JG, Wu YC, Chen HS. Novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Clin Endocrinol (Oxf). 2005 Mar;62(3):336-42. PMID:15730416 doi:10.1111/j.1365-2265.2005.02219.x
- ↑ Klein RD, Salih S, Bessoni J, Bale AE. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID:15714081 doi:10.109701.GIM.0000153663.62300.F8
- ↑ Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A. Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat. 1999;13(1):54-60. PMID:9888389 doi:<54::AID-HUMU6>3.0.CO;2-K 10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K
- ↑ Pannett AA, Kennedy AM, Turner JJ, Forbes SA, Cavaco BM, Bassett JH, Cianferotti L, Harding B, Shine B, Flinter F, Maidment CG, Trembath R, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf). 2003 May;58(5):639-46. PMID:12699448
- ↑ Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, Nordenskjold M, Pearce CJ, Carmichael D, Larsson C, Harris PE. A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. Am J Hum Genet. 1998 Nov;63(5):1544-9. PMID:9792884 doi:10.1086/302097
- ↑ Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, Ito K, Shingu K, Kobayashi S, Amano J, Fukushima Y. Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism. Am J Med Genet. 1998 Nov 16;80(3):221-2. PMID:9843042
- ↑ Honda M, Tsukada T, Tanaka H, Maruyama K, Yamaguchi K, Obara T, Yamaji T, Ishibashi M. A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism. Eur J Endocrinol. 2000 Feb;142(2):138-43. PMID:10664521
- ↑ Kassem M, Kruse TA, Wong FK, Larsson C, Teh BT. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab. 2000 Jan;85(1):165-7. PMID:10634381
- ↑ Perrier ND, Villablanca A, Larsson C, Wong M, Ituarte P, Teh BT, Clark OH. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. Epub 2002 May 21. PMID:12016470 doi:10.1007/s00268-002-6617-9
- ↑ Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene. 2001 Aug 16;20(36):4917-25. PMID:11526476 doi:10.1038/sj.onc.1204529
- ↑ Kaji H, Canaff L, Lebrun JJ, Goltzman D, Hendy GN. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3837-42. Epub 2001 Mar 13. PMID:11274402 doi:10.1073/pnas.061358098
- ↑ Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X. Menin associates with FANCD2, a protein involved in repair of DNA damage. Cancer Res. 2003 Jul 15;63(14):4204-10. PMID:12874027
- ↑ Lin SY, Elledge SJ. Multiple tumor suppressor pathways negatively regulate telomerase. Cell. 2003 Jun 27;113(7):881-9. PMID:12837246
- ↑ Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004 Feb 27;13(4):587-97. PMID:14992727
- ↑ Klossowski S, Miao H, Kempinska K, Wu T, Purohit T, Kim E, Linhares BM, Chen D, Jih G, Perkey E, Huang H, He M, Wen B, Wang Y, Yu K, Lee SC, Danet-Desnoyers G, Trotman W, Kandarpa M, Cotton A, Abdel-Wahab O, Lei H, Dou Y, Guzman M, Peterson L, Gruber TA, Choi SM, Sun D, Ren P, Li LS, Liu Y, Burrows FJ, Maillard I, Cierpicki T, Grembecka J. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2019 Dec 19. pii: 129126. doi: 10.1172/JCI129126. PMID:31855575 doi:http://dx.doi.org/10.1172/JCI129126
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