MN1 (gene) explained

MN1 is a gene found on human chromosome 22, with gene map locus 22q12.3-qter.^[1] Its official full name is meningioma (disrupted in balanced translocation) 1 because it is disrupted by a balanced translocation (4;22) in a meningioma.

Function

MN1 is a transcription coregulator that enhances or represses gene expression through direct or indirect interaction with the gene regulatory machinery. Reported interactions include the BAF (SWI/SNF) complex.^[2] RAC3 and p300.^[3] MN1 can act as a coactivator of several transcription factors, including RAR/RXR and the vitamin D receptor.^[4] In AML, MN1 binds to genomic sites enriched for binding motifs of ETS factors as well as hematopoietic transcription factors such as RUNX1, GATA2, HOXA cluster genes, and MEIS1. MN1 induces a hematopoietic stem and progenitor gene expression program centered on HOXA cluster genes, particularly HOXA9 and MEIS1 via its interaction with the BAF complex^[5]

Clinical significance

The translocation of MN1 was first reported in meningioma. A substantial percentage of primitive neuro-ectodermal tumors (PNET) have MN1 translocations^[6] Several different partners were described, although in many cases no fusion partner was identified. MN1 transloations also occur in up to 2% of acute myeloid leukemia (AML)^[7] Described fusion partners include ETV6, STAT3 and FLI1.^{[8] [9]} About 50% of fusions are out of frame and result in high expression of MN1 via enhancer hijacking.High MN1 expression in AML and MDS is associated with poor outcome ^{[10] [11] [12] [13] [14] [15] [16]}

Mutations in this gene have been associated with cleft palate^{[17] [18] [19]} and an atypical form of rhombencephalosynapsis.^[20]

Further reading

• Kawagoe H, Grosveld GC . MN1-TEL myeloid oncoprotein expressed in multipotent progenitors perturbs both myeloid and lymphoid growth and causes T-lymphoid tumors in mice . Blood . 106 . 13 . 4278–86 . December 2005 . 16081688 . 1895241 . 10.1182/blood-2005-04-1674 .
• Schroeder T, Czibere A, Zohren F, Aivado M, Gattermann N, Germing U, Haas R . Meningioma 1 gene is differentially expressed in CD34 positive cells from bone marrow of patients with myelodysplastic syndromes with the highest expression in refractory anemia with excess of blasts and secondary acute myeloid leukemia . Leukemia & Lymphoma . 50 . 6 . 1043–6 . June 2009 . 19391034 . 10.1080/10428190902913591 . 38372641 .
• Meester-Smoor MA, Janssen MJ, Grosveld GC, de Klein A, van IJcken WF, Douben H, Zwarthoff EC . MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression . Carcinogenesis . 29 . 10 . 2025–34 . October 2008 . 18632758 . 3202306 . 10.1093/carcin/bgn168 .
• Carella C, Bonten J, Sirma S, Kranenburg TA, Terranova S, Klein-Geltink R, Shurtleff S, Downing JR, Zwarthoff EC, Liu PP, Grosveld GC . 6 . MN1 overexpression is an important step in the development of inv(16) AML . Leukemia . 21 . 8 . 1679–90 . August 2007 . 17525718 . 10.1038/sj.leu.2404778 . 21088872 .
• Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S, Schlenk RF, Dohner K, Hinrichsen T, Rudolph C, Schambach A, Baum C, Schlegelberger B, Dohner H, Ganser A, Humphries RK . 6 . MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML . Blood . 110 . 5 . 1639–47 . September 2007 . 17494859 . 10.1182/blood-2007-03-080523 . free .
• Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H . 6 . Toward a confocal subcellular atlas of the human proteome . Molecular & Cellular Proteomics . 7 . 3 . 499–508 . March 2008 . 18029348 . 10.1074/mcp.M700325-MCP200 . free .
• Kawagoe H, Grosveld GC . Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9 . Blood . 106 . 13 . 4269–77 . December 2005 . 16105979 . 1895240 . 10.1182/blood-2005-04-1679 .
• Kandilci A, Grosveld GC . Reintroduction of CEBPA in MN1-overexpressing hematopoietic cells prevents their hyperproliferation and restores myeloid differentiation . Blood . 114 . 8 . 1596–606 . August 2009 . 19561324 . 2731639 . 10.1182/blood-2009-02-205443 .
• Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C . 6 . Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling . Gut . 58 . 8 . 1078–83 . August 2009 . 19240061 . 10.1136/gut.2008.169052 . 17111427 .
• Gastier JM, Brody T, Pulido JC, Businga T, Sunden S, Hu X, Maitra S, Buetow KH, Murray JC, Sheffield VC, Boguski M, Duyk GM, Hudson TJ . 6 . Development of a screening set for new (CAG/CTG)n dynamic mutations . Genomics . 32 . 1 . 75–85 . February 1996 . 8786123 . 10.1006/geno.1996.0078 .
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I . 6 . A genome annotation-driven approach to cloning the human ORFeome . Genome Biology . 5 . 10 . R84 . 2004 . 15461802 . 545604 . 10.1186/gb-2004-5-10-r84 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . 6 . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Meester-Smoor MA, Molijn AC, Zhao Y, Groen NA, Groffen CA, Boogaard M, van Dalsum-Verbiest D, Grosveld GC, Zwarthoff EC . 6 . The MN1 oncoprotein activates transcription of the IGFBP5 promoter through a CACCC-rich consensus sequence . Journal of Molecular Endocrinology . 38 . 1–2 . 113–25 . February 2007 . 17242174 . 10.1677/jme.1.02110 . free .

Notes and References

1. Lekanne Deprez RH, Riegman PH, Groen NA, Warringa UL, van Biezen NA, Molijn AC, Bootsma D, de Jong PJ, Menon AG, Kley NA . 6 . Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma . Oncogene . 10 . 8 . 1521–8 . April 1995 . 7731706 .
2. Riedel SS, Lu C, Xie HM, Nestler K, Vermunt MW, Lenard A, Bennett L, Speck NA, Hanamura I, Lessard JA, Blobel GA, Garcia BA, Bernt KM . 6 . Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML . Molecular Cell . 81 . 11 . 2332–2348.e9 . June 2021 . 33974912 . 10.1016/j.molcel.2021.04.014. 1097-2765 . 8380056 .
3. van Wely KH, Molijn AC, Buijs A, Meester-Smoor MA, Aarnoudse AJ, Hellemons A, den Besten P, Grosveld GC, Zwarthoff EC . 6 . The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription . Oncogene . 22 . 5 . 699–709 . February 2003 . 12569362 . 10.1038/sj.onc.1206124 . 10105930 . free .
4. Sutton AL, Zhang X, Ellison TI, Macdonald PN . The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation . Molecular Endocrinology . 19 . 9 . 2234–44 . September 2005 . 15890672 . 10.1210/me.2005-0081 . free .
5. Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F, Park G, Hamwi I, Palmqvist L, Lai CK, Leung M, Lin G, Chaturvedi A, Thakur BK, Iwasaki M, Bilenky M, Thiessen N, Robertson G, Hirst M, Kent D, Wilson NK, Göttgens B, Eaves C, Cleary ML, Marra M, Ganser A, Humphries RK . 6 . Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex . Cancer Cell . 20 . 1 . 39–52 . July 2011 . 21741595 . 10.1016/j.ccr.2011.06.020 . 3951989 .
6. Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M . 6 . New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs . Cell . 164 . 5 . 1060–1072 . February 2016 . 26919435 . 10.1016/j.cell.2016.01.015 . 5139621 .
7. Wang T, Chen X, Hui S, Ni J, Yin Y, Cao W, Zhang Y, Wang X, Ma X, Cao P, Liu M, Chen KN, Wang F, Zhang Y, Nie D, Yuan L, Liu H . 6 . Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12) . Cancer Gene Therapy . 27 . 10–11 . 810–818 . November 2020 . 31902945 . 10.1038/s41417-019-0159-x . 7661342 .
8. Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D, Geurts van Kessel A, Riegman P, Lekanne Deprez R, Zwarthoff E, Hagemeijer A . 6 . Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11 . Oncogene . 10 . 8 . 1511–9 . April 1995 . 7731705 .
9. Dang J, Nance S, Ma J, Cheng J, Walsh MP, Vogel P, Easton J, Song G, Rusch M, Gedman AL, Koss C, Downing JR, Gruber TA . 6 . AMKL chimeric transcription factors are potent inducers of leukemia . Leukemia . 31 . 10 . 2228–2234 . October 2017 . 28174417 . 10.1038/leu.2017.51 . 5791746 .
10. Heuser M, Beutel G, Krauter J, Döhner K, von Neuhoff N, Schlegelberger B, Ganser A . High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics . Blood . 108 . 12 . 3898–905 . December 2006 . 16912223 . 10.1182/blood-2006-04-014845 . 16434975 .
11. Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger S, Haferlach T . Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia . Genes, Chromosomes & Cancer . 51 . 3 . 257–65 . March 2012 . 22072540 . 10.1002/gcc.20950 . 205828447 .
12. Langer C, Marcucci G, Holland KB, Radmacher MD, Maharry K, Paschka P, Whitman SP, Mrózek K, Baldus CD, Vij R, Powell BL, Carroll AJ, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD . 6 . Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study . Journal of Clinical Oncology . 27 . 19 . 3198–204 . July 2009 . 19451432 . 10.1200/JCO.2008.20.6110 . 2716941 .
13. Metzeler KH, Dufour A, Benthaus T, Hummel M, Sauerland MC, Heinecke A, Berdel WE, Büchner T, Wörmann B, Mansmann U, Braess J, Spiekermann K, Hiddemann W, Buske C, Bohlander SK . 6 . ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays . Journal of Clinical Oncology . 27 . 30 . 5031–8 . October 2009 . 19752345 . 10.1200/JCO.2008.20.5328 . free .
14. Schwind S, Marcucci G, Kohlschmidt J, Radmacher MD, Mrózek K, Maharry K, Becker H, Metzeler KH, Whitman SP, Wu YZ, Powell BL, Baer MR, Kolitz JE, Carroll AJ, Larson RA, Caligiuri MA, Bloomfield CD . 6 . Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia . Blood . 118 . 15 . 4188–98 . October 2011 . 21828125 . 10.1182/blood-2011-06-357764 . 3291490 .
15. Xiang L, Li M, Liu Y, Cen J, Chen Z, Zhen X, Xie X, Cao X, Gu W . 6 . The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia . Annals of Hematology . 92 . 8 . 1063–9 . August 2013 . 23515710 . 10.1007/s00277-013-1729-x . 23939296 .
16. Grosveld GC . MN1, a novel player in human AML . Blood Cells, Molecules & Diseases . 2007 . 39 . 3 . 336–9 . 17698380 . 10.1016/j.bcmd.2007.06.009 . 2387274 .
17. Shu L, He D, Wu D, Peng Y, Xi H, Mao X, Wang H . MN1 gene loss-of-function mutation causes cleft palate in a pedigree . Brain . 144 . 2 . e18 . March 2021 . 33351070 . 10.1093/brain/awaa431 . 7940500 .
18. Breckpot J, Anderlid BM, Alanay Y, Blyth M, Brahimi A, Duban-Bedu B, Gozé O, Firth H, Yakicier MC, Hens G, Rayyan M, Legius E, Vermeesch JR, Devriendt K . 6 . Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate . European Journal of Human Genetics . 24 . 1 . 51–8 . January 2016 . 25944382 . 10.1038/ejhg.2015.65 . 4795238 .
19. Meester-Smoor MA, Vermeij M, van Helmond MJ, Molijn AC, van Wely KH, Hekman AC, Vermey-Keers C, Riegman PH, Zwarthoff EC . 6 . Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton . Molecular and Cellular Biology . 25 . 10 . 4229–36 . May 2005 . 15870292 . 10.1128/MCB.25.10.4229-4236.2005 . 1087735 .
20. Mak CC, Doherty D, Lin AE, Vegas N, Cho MT, Viot G, Dimartino C, Weisfeld-Adams JD, Lessel D, Joss S, Li C, Gonzaga-Jauregui C, Zarate YA, Ehmke N, Horn D, Troyer C, Kant SG, Lee Y, Ishak GE, Leung G, Barone Pritchard A, Yang S, Bend EG, Filippini F, Roadhouse C, Lebrun N, Mehaffey MG, Martin PM, Apple B, Millan F, Puk O, Hoffer MJ, Henderson LB, McGowan R, Wentzensen IM, Pei S, Zahir FR, Yu M, Gibson WT, Seman A, Steeves M, Murrell JR, Luettgen S, Francisco E, Strom TM, Amlie-Wolf L, Kaindl AM, Wilson WG, Halbach S, Basel-Salmon L, Lev-El N, Denecke J, Vissers LE, Radtke K, Chelly J, Zackai E, Friedman JM, Bamshad MJ, Nickerson DA, Reid RR, Devriendt K, Chae JH, Stolerman E, McDougall C, Powis Z, Bienvenu T, Tan TY, Orenstein N, Dobyns WB, Shieh JT, Choi M, Waggoner D, Gripp KW, Parker MJ, Stoler J, Lyonnet S, Cormier-Daire V, Viskochil D, Hoffman TL, Amiel J, Chung BH, Gordon CT . 6 . MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis . Brain . 143 . 1 . 55–68 . January 2020 . 31834374 . 7962909 . 10.1093/brain/awz379 .