Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q
Ademà, Vera (Department of Translational Hematology and Oncology Research. Lerner Research Institute. Cleveland Clinic. Taussig Cancer Institute)
Palomo Sanchís, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Walter, Wencke (Munich Leukemia Laboratory)
Mallo, Maria del Mar (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Hutter, Stephan (Munich Leukemia Laboratory)
La Framboise, Thomas (Department of Genetics and Genome Sciences. Case Western Reserve University)
Arenillas, Leonor (Institut Hospital del Mar d'Investigacions Mèdiques)
Meggendorfer, Manja (Munich Leukemia Laboratory)
Radivoyevitch, Tomas (Department of Translational Hematology and Oncology Research. Lerner Research Institute. Cleveland Clinic. Taussig Cancer Institute)
Xicoy, Blanca (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Pellagatti, Andrea (Blood Cancer UK Molecular Haematology Unit. Nuffield Division of Clinical Laboratory Sciences. Radcliffe Department of Medicine. University of Oxford and Oxford BRC Haematology Theme)
Haferlach, Claudia (Munich Leukemia Laboratory)
Boultwood, Jacqueline (University of Oxford. Radcliffe Department of Medicine)
Kern, Wolfgang (Munich Leukemia Laboratory)
Visconte, Valeria (Department of Translational Hematology and Oncology Research. Lerner Research Institute. Cleveland Clinic. Taussig Cancer Institute)
Sekeres, Mikkael (Leukemia Program. Department of Hematology and Medical Oncology. Cleveland Clinic. Cleveland Clinic Taussig Cancer Institute)
Barnard, John (Department of Quantitative Health Sciences. Cleveland Clinic. Lerner Research Institute)
Haferlach, Torsten (Munich Leukemia Laboratory)
Sole, F (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Maciejewski, Jaroslaw (Department of Translational Hematology and Oncology Research. Lerner Research Institute. Cleveland Clinic. Taussig Cancer Institute)

Data:	2022
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017 SGR288 Ministerio de Economía y Competitividad PI/14/00013 Ministerio de Economía y Competitividad PI/17/0575
Nota:	Altres ajuts: Torsten Haferlach Leukemia Diagnostics Foundation; US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, R01 CA217992, R01 LM013067, R21 CA248138; Edward P. Evans Foundation; Blood Cancer UK, grants 13042 and 19004; Fundació Internacional Josep Carreras and "la Caixa" Foundation.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Myelodysplastic syndromes ; 5q deletion ; Haploinsufficiency ; TP53 ; CSNK1A1
Publicat a:	EBioMedicine, Vol. 80 (june 2022) , art. 104059, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2022.104059
PMID: 35617825

13 p, 3.0 MB

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