Grossmann, Vera, Tiacci, Enrico, Holmes, Antony B., Kohlmann, Alexander, Martelli, Maria Paola, Kern, Wolfgang, Spanhol-Rosseto, Ariele, Klein, Hans-Ulrich ORCID: 0000-0002-6382-9428, Dugas, Martin, Schindela, Sonja, Trifonov, Vladimir, Schnittger, Susanne, Haferlach, Claudia, Bassan, Renato, Wells, Victoria A., Spinelli, Orietta, Chan, Joseph ORCID: 0000-0001-5249-7395, Rossi, Roberta, Baldoni, Stefano ORCID: 0000-0002-5420-5672, De Carolis, Luca, Goetze, Katharina, Serve, Hubert ORCID: 0000-0001-8472-5516, Peceny, Rudolf, Kreuzer, Karl-Anton, Oruzio, Daniel, Specchia, Giorgina ORCID: 0000-0002-2479-9529, Di Raimondo, Francesco ORCID: 0000-0002-7749-0293, Fabbiano, Francesco, Sborgia, Marco, Liso, Arcangelo ORCID: 0000-0001-5638-227X, Farinelli, Laurent, Rambaldi, Alessandro ORCID: 0000-0002-3739-7502, Pasqualucci, Laura, Rabadan, Raul ORCID: 0000-0001-7946-9255, Haferlach, Torsten and Falini, Brunangelo (2011). Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood, 118 (23). S. 6153 - 6164. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardiodental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis. (Blood. 2011;118(23):6153-6163)

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Grossmann, VeraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tiacci, EnricoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holmes, Antony B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohlmann, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martelli, Maria PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kern, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spanhol-Rosseto, ArieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Hans-UlrichUNSPECIFIEDorcid.org/0000-0002-6382-9428UNSPECIFIED
Dugas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schindela, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifonov, VladimirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnittger, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haferlach, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bassan, RenatoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wells, Victoria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spinelli, OriettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, JosephUNSPECIFIEDorcid.org/0000-0001-5249-7395UNSPECIFIED
Rossi, RobertaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldoni, StefanoUNSPECIFIEDorcid.org/0000-0002-5420-5672UNSPECIFIED
De Carolis, LucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goetze, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serve, HubertUNSPECIFIEDorcid.org/0000-0001-8472-5516UNSPECIFIED
Peceny, RudolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuzer, Karl-AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oruzio, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Specchia, GiorginaUNSPECIFIEDorcid.org/0000-0002-2479-9529UNSPECIFIED
Di Raimondo, FrancescoUNSPECIFIEDorcid.org/0000-0002-7749-0293UNSPECIFIED
Fabbiano, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sborgia, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liso, ArcangeloUNSPECIFIEDorcid.org/0000-0001-5638-227XUNSPECIFIED
Farinelli, LaurentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rambaldi, AlessandroUNSPECIFIEDorcid.org/0000-0002-3739-7502UNSPECIFIED
Pasqualucci, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabadan, RaulUNSPECIFIEDorcid.org/0000-0001-7946-9255UNSPECIFIED
Haferlach, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falini, BrunangeloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-484717
DOI: 10.1182/blood-2011-07-365320
Journal or Publication Title: Blood
Volume: 118
Number: 23
Page Range: S. 6153 - 6164
Date: 2011
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACUTE MYELOGENOUS LEUKEMIA; CYTOPLASMIC NUCLEOPHOSMIN; GENE; EXPRESSION; COMPLEX; PROGNOSIS; DIAGNOSIS; PROFILE; DNMT3A; DOMAINMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48471

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