Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q

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• dc.contributor.author Ademá, Veraor
• dc.contributor.author Palomo, Laura
• dc.contributor.author Walter, Wencke
• dc.contributor.author Mallo, Mar
• dc.contributor.author Hutter, Stephan
• dc.contributor.author La Framboise, Thomas
• dc.contributor.author Arenillas Rocha, Leonor
• dc.contributor.author Meggendorfer, Manja
• dc.contributor.author Radivoyevitch, Tomas
• dc.contributor.author Xicoy, Blanca
• dc.contributor.author Pellagatti, Andrea
• dc.contributor.author Haferlach, Claudia
• dc.contributor.author Boultwood, Jacqueline
• dc.contributor.author Kern, Wolfgang
• dc.contributor.author Visconte, Valeria
• dc.contributor.author Sekeres, Mikkael
• dc.contributor.author Barnard, John
• dc.contributor.author Haferlach, Torsten
• dc.contributor.author Solé Ristol, Francesc
• dc.contributor.author Maciejewski, Jaroslaw P.
• dc.date.accessioned 2022-10-24T06:35:18Z
• dc.date.available 2022-10-24T06:35:18Z
• dc.date.issued 2022
• dc.description.abstract Background: haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified. Methods: here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)]. Findings: Del(5q) resulted as founder (better prognosis) or secondary hit (preceded by TP53 mutations). Using Bayesian prediction analyses on 57 HI marker genes we established the minimal del(5q) gene signature that distinguishes del(5q) from diploid cases. Clusters of diploid cases mimicking the del(5q) signature support the overall importance of del(5q) genes in the pathogenesis of MDS in general. Sub-clusters within del(5q) patients pointed towards the inherent intrapatient heterogeneity of HI genes. Interpretation: the underlying clonal expansion drive results from a balance between the "HI-driver" genes (e.g., CSNK1A1, CTNNA1, TCERG1) and the proapoptotic "HI-anti-drivers" (e.g., RPS14, PURA, SIL1). The residual essential clonal expansion drive allows for selection of accelerator mutations such as TP53 (denominating poor) and CSNK1A1 mutations (with a better prognosis) which overcome pro-apoptotic genes (e.g., p21, BAD, BAX), resulting in a clonal expansion. In summary, we describe the complete picture of del(5q) MN identifying the crucial genes, gene clusters and clonal hierarchy dictating the clinical course of del(5q) patients.
• dc.format.mimetype application/pdf
• dc.identifier.citation Adema V, Palomo L, Walter W, Mallo M, Hutter S, La Framboise T, et al. Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q. EBioMedicine. 2022 Jun; 80: 104059. DOI: 10.1016/j.ebiom.2022.104059
• dc.identifier.doi http://dx.doi.org/10.1016/j.ebiom.2022.104059
• dc.identifier.issn 2352-3964
• dc.identifier.uri http://hdl.handle.net/10230/54544
• dc.language.iso eng
• dc.publisher Elsevier
• dc.rights Copyright © 2022 Adema V, Palomo L, Walter W, Mallo M, Hutter S, La Framboise T. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword 5q deletion
• dc.subject.keyword CSNK1A1
• dc.subject.keyword Haploinsufficiency
• dc.subject.keyword Myelodysplastic syndromes
• dc.subject.keyword TP53
• dc.title Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion