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

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 exp...

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Detalhes bibliográficos
Autores: Ademà, Vera|||0000-0001-6051-4378, Palomo Sanchís, Laura|||0000-0003-3176-6271, Walter, Wencke, Mallo, Maria del Mar|||0000-0001-7741-498X, Hutter, Stephan|||0000-0003-2432-8898, La Framboise, Thomas, Arenillas, Leonor|||0000-0002-9020-8766, Meggendorfer, Manja, Radivoyevitch, Tomas, Xicoy, Blanca|||0000-0002-0295-1307, Pellagatti, Andrea, Haferlach, Claudia, Boultwood, Jacqueline|||0000-0002-4330-2928, Kern, Wolfgang|||0000-0002-6452-2874, Visconte, Valeria|||0000-0002-2993-1509, Sekeres, Mikkael|||0000-0003-2009-6524, Barnard, John|||0000-0003-2403-8268, Haferlach, T.|||0000-0003-0196-2837, Sole, F.|||0000-0002-3251-2161, Maciejewski, Jaroslaw|||0000-0002-6837-4346
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270658
Acesso em linha:https://ddd.uab.cat/record/270658
https://dx.doi.org/urn:doi:10.1016/j.ebiom.2022.104059
Access Level:acceso abierto
Palavra-chave:Myelodysplastic syndromes
5q deletion
Haploinsufficiency
TP53
CSNK1A1
Descrição
Resumo: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.

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