A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure.
EVI1
MECOM
MECOM-AS
MPL
bone marrow failure
inherited thrombocytopenia
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
revised:
21
06
2023
received:
31
03
2023
accepted:
21
07
2023
medline:
29
11
2023
pubmed:
23
8
2023
entrez:
23
8
2023
Statut:
ppublish
Résumé
MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1. The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood. In a paediatric patient affected by severe thrombocytopenia, we identified a novel variant of the MECOM gene (p.P634L), whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor. Moreover, we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT.
Substances chimiques
Transcription Factors
0
MPL protein, human
143641-95-6
Receptors, Thrombopoietin
0
MECOM protein, human
0
MDS1 and EVI1 Complex Locus Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
852-859Subventions
Organisme : Italian Ministry of Health
ID : RC 28/2022
Organisme : Associazione di Promozione Sociale "Genitori in fuga"
Informations de copyright
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Savoia A. Molecular basis of inherited thrombocytopenias. Clin Genet. 2016;89(2):154-162. https://doi.org/10.1111/cge.12607
Noris P, Pecci A. Hereditary thrombocytopenias: a growing list of disorders. Hematology. 2017;2017(1):385-399. https://doi.org/10.1182/asheducation-2017.1.385
Niihori T, Ouchi-Uchiyama M, Sasahara Y, Kaneko T, Hashii Y, Irie M, et al. Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic thrombocytopenia. Am J Hum Genet. 2015;97(6):848-854. https://doi.org/10.1016/j.ajhg.2015.10.010
Germeshausen M, Ancliff P, Estrada J, Metzler M, Ponstingl E, Rütschle H, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596. https://doi.org/10.1182/bloodadvances.2018016501
Fears S, Mathieu C, Zeleznik-Le N, Huang S, Cothi DE, Rowley JD, et al. Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Proc Natl Acad Sci USA. 1996;93(4):1642-1647. https://doi.org/10.1073/pnas.93.4.1642
Glass C, Wuertzer C, Cui X, Bi Y, Davuluri R, Xiao YY, et al. Global identification of EVI1 target genes in acute myeloid leukemia. PLoS ONE. 2013;8(6):e67134. https://doi.org/10.1371/journal.pone.0067134
Perkins AS, Mercer JA, Jenkins NA, Griec OC, Copeland NG. Patterns of Evi-1 expression in embryonic and adult tissues suggest that Evi-1 plays an important regulatory role in mouse development. Development. 1991;111(2):479-487. https://doi.org/10.1242/dev.111.2.479
Delwel R, Funabiki T, Kreider BL, Cibeu S, Morishita K, Ihle JN. Four of the seven zinc fingers of the Evi-1 myeloid-transforming gene are required for sequence-specific binding to GA(C/T)AAGA(T/C)AAGATAA. Mol Cell Biol. 1993;13(7):4291-4300. https://doi.org/10.1128/mcb.13.7.4291-4300.1993
Funabiki T, Kreider BL, Benet N, Ihle JN. The carboxyl domain of zinc fingers of the Evi-1 myeloid transforming gene binds a consensus sequence of GAAGATGAG. Oncogene. 1994;9(6):1575-1581.
Yuasa H, Oike Y, Iwama A, Nishikata I, Sugiyama D, Perkins A, et al. Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression. EMBO J. 2005;24(11):1976-1987. https://doi.org/10.1038/sj.emboj.7600679
Wieser R. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene. 2007;396(2):346-357. https://doi.org/10.1016/j.gene.2007.04.012
Lord SV, Jimenez JE, Kroeger ZA, Patrick CS, Tao S, Hernandez N, et al. A MECOM variant in an African American child with radioulnar synostosis and thrombocytopenia. Clin Dysmorphol. 2018;27(1):9-11. https://doi.org/10.1097/MCD.0000000000000200
Osumi T, Tsujimoto SI, Nakabayashi K, Taniguchi M, Shirai R, Yoshida M, et al. Somatic MECOM mosaicism in a patient with congenital bone marrow failure without a radial abnormality. Pediatr Blood Cancer. 2018;65(6):1-3. https://doi.org/10.1002/pbc.26959
Walne A, Tummala H, Ellison A, Cardoso S, Sidhu J, Sciuccati G, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103:284-287.
Loganathan A, Munirathnam D, Ravikumar T. A novel mutation in the MECOM gene causing radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT-2) in an infant. Pediatr Blood Cancer. 2019;66(4):2-3. https://doi.org/10.1002/pbc.27574
Shen F, Yang Y, Zheng Y, Li P, Luo Z, Fu Y, et al. MECOM-related disorder: radioulnar synostosis without hematological aberration due to unique variants. Genet Med. 2022;24(5):1139-1147. https://doi.org/10.1016/j.gim.2022.01.021
Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131(7):717-732. https://doi.org/10.1182/blood-2017-09-806489
Ripperger T, Hofmann W, Koch JC, Shirneshan K, Haase D, Wulf G, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58. https://doi.org/10.3324/haematol.2017.178723
Marzollo A, Maestrini G, la Starza R, Elia L, Malfona F, Pierini T, et al. A novel germline variant in PIK3R1 results in SHORT syndrome associated with TAL/LMO T-cell acute lymphoblastic leukemia. Am J Hematol. 2020;95(12):E335-E338. https://doi.org/10.1002/ajh.25998
Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y, Hirai H. Evi-1 raises AP-1 activity and stimulates c-fos promoter transactivation with dependence on the second zinc finger domain. J Biol Chem. 1994;269(39):24020-24026. https://doi.org/10.1016/s0021-9258(19)51041-9
Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y, et al. Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells. Oncogene. 2009;28(49):4364-4374. https://doi.org/10.1038/onc.2009.288
Buonamici S, Li D, Chi Y, Zhao R, Wang X, Brace L, et al. EVI1 induces myelodysplastic syndrome in mice. J Clin Investig. 2005;115(8):2296. https://doi.org/10.1172/jci21716c1
Sunohara M, Morikawa S, Sato T, Miyado M, Sato I, Sato T, et al. Promoter regulatory motifs involved in c-mpl gene expression induced by PMA. Cell Biol Int. 2008;32(6):692-697. https://doi.org/10.1016/j.cellbi.2008.01.004
Mignotte V, Vigon I, de Crevecoeur EB, Romeo PH, Lemarchandel V, Chretien S. Structure and transcription of the human C-MPL gene (MPL). Genomics. 1994;20(1):5-12. https://doi.org/10.1006/geno.1994.1120
Murone M, Carpenter DA, de Sauvage FJ. Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem Cells. 1998;16(1):1-6. https://doi.org/10.1002/stem.160001
Weizmann D, Pincez T, Roussy M, Vaillancourt N, Kats VS, Champagne J, et al. New MECOM variant in a child with severe neonatal cytopenias spontaneously resolving. Pediatr Blood Cancer. 2020;67(5):3-5. https://doi.org/10.1002/pbc.28215
Datta SS, Basu S, Ghara N, Kole P, Khemka P. Utility of platelet cross-matching in a case of neonatal alloimmune thrombocytopenia associated with a de novo MECOM variant. Blood Res. 2021;56(1):53-56. https://doi.org/10.5045/br.2021.2020299
Nielsen M, Vermont CL, Aten E, Ruivenkamp CAL, van Herrewegen F, Santen GWE, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet. 2012;49(9):598-600. https://doi.org/10.1136/jmedgenet-2012-100990
Bartholomew C, Kilbey A, Clark AM, Walker M. The Evi-1 proto-oncogene encodes a transcriptional repressor activity associated with transformation. Oncogene. 1997;14(5):569-577. https://doi.org/10.1038/sj.onc.1200864
Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor β signaling. Blood. 2001;97(9):2815-2822. https://doi.org/10.1182/blood.V97.9.2815
Megy K, Downes K, Morel-Kopp MC, Bastida JM, Brooks S, Bury L, et al. GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: communication from the ISTH SSC subcommittee on genomics in thrombosis and hemostasis. J Thromb Haemost. 2021;19(10):2612-2617. https://doi.org/10.1111/jth.15459
Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, et al. Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell. 2008;3(2):207-220. https://doi.org/10.1016/j.stem.2008.06.002
Yan XQ, Lacey DL, Saris C, Mu S, Hill D, Hawley RG, et al. Ectopic overexpression of c-mpl by retroviral-mediated gene transfer suppressed megakaryopoiesis but enhanced erythropoiesis in mice. Exp Hematol. 1999;27(9):1409-1417. https://doi.org/10.1016/S0301-472X(99)00069-7
Wicke DC, Meyer J, Buesche G, Heckl D, Kreipe H, Li Z, et al. Gene therapy of Mpl deficiency: challenging balance between leukemia and pancytopenia. Mol Ther. 2010;18(2):343-352. https://doi.org/10.1038/mt.2009.233
Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell. 2014;15(4):507-522. https://doi.org/10.1016/j.stem.2014.07.005
Kataoka K, Sato T, Yoshimi A, Goyama S, Tsuruta T, Kobayashi H, et al. Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity. J Exp Med. 2011;208(12):2403-2416. https://doi.org/10.1084/jem.20110447
Paredes R, Schneider M, Stevens A, White DJ, Williamson AJK, Muter J, et al. EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. Nucleic Acids Res. 2018;46(15):7662-7674. https://doi.org/10.1093/nar/gky536
Voit RA, Tao L, Yu F, Cato LD, Cohen B, Fleming TJ, et al. A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia. Nat Immunol. 2023;24(1):69-83. https://doi.org/10.1038/s41590-022-01370-4
Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood. 2008;111(9):4446-4455. https://doi.org/10.1182/blood-2007-08-019729
Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124(18):2775-2783. https://doi.org/10.1182/blood-2014-05-526285
Marzollo A, Calore E, Tumino M, Pillon M, Gazzola MV, Destro R, et al. Treosulfan-based conditioning regimen in sibling and alternative donor hematopoietic stem cell transplantation for children with sickle cell disease. Mediterr J Hematol Infect Dis. 2017;9(1):1-9. https://doi.org/10.4084/mjhid.2017.014
Irie M, Niihori T, Nakano T, Suzuki T, Katayama S, Moriya K, et al. Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome. Int J Hematol. 2022;117:598-606. https://doi.org/10.1007/s12185-022-03505-7
Germeshausen M, Ballmaier M. CAMT-MPL: congenital amegakaryocytic thrombocytopenia caused by MPL mutations-heterogeneity of a monogenic disorder-a comprehensive analysis of 56 patients. Haematologica. 2021;106(9):2439-2448. https://doi.org/10.3324/haematol.2020.257972
Seo A, Ben-Harosh M, Sirin M, Stein J, Dgany O, Kaplelushnik J, et al. Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin. Blood. 2017;130(7):875-880. https://doi.org/10.1182/blood-2017-02-768036
Pecci A, Ragab I, Bozzi V, de Rocco D, Barozzi S, Giangregorio T, et al. Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim. EMBO Mol Med. 2018;10(1):63-75. https://doi.org/10.15252/emmm.201708168
Capaci V, Adam E, Bar-Joseph I, Faleschini M, Pecci A, Savoia A. Defective binding of ETS1 and STAT4 due to a mutation in the promoter region of THPO as a novel mechanism of congenital amegakaryocytic thrombocytopenia. Haematologica. 2022;108:1385-1393. https://doi.org/10.3324/haematol.2022.281392