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

Bayes Theorem Chromosome Deletion Chromosomes, Human, Pair 5 Guanine Nucleotide Exchange Factors / genetics Haploinsufficiency / genetics Humans Mutation Myelodysplastic Syndromes / diagnosis Transcriptional Elongation Factors / genetics
5q deletion CSNK1A1 Haploinsufficiency Myelodysplastic syndromes TP53

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Jun 2022
Historique:
received: 29 11 2021
revised: 28 04 2022
accepted: 29 04 2022
pubmed: 27 5 2022
medline: 15 6 2022
entrez: 26 5 2022
Statut: ppublish

Résumé

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. Here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)]. 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. 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. Torsten Haferlach Leukemia Diagnostics Foundation. US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, and a grant from Edward P. Evans Foundation.

Sections du résumé

BACKGROUND 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 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 RESULTS
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 CONCLUSIONS
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.
FUNDING BACKGROUND
Torsten Haferlach Leukemia Diagnostics Foundation. US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, and a grant from Edward P. Evans Foundation.

Identifiants

DOI: 10.1016/j.ebiom.2022.104059 PMID: 35617825 PMC: PMC9130225
pubmed: 35617825
pii: S2352-3964(22)00240-7
doi: 10.1016/j.ebiom.2022.104059
pmc: PMC9130225
pii:
doi:

Substances chimiques

Guanine Nucleotide Exchange Factors 0
SIL1 protein, human 0
TCERG1 protein, human 0
Transcriptional Elongation Factors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104059

Subventions

Organisme : NCI NIH HHS
ID : R21 CA249138
Pays : United States

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

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Auteurs

Vera Adema (V)

Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Laura Palomo (L)

Myelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.

Wencke Walter (W)

MLL Munich Leukemia Laboratory, Munich, Germany.

Mar Mallo (M)

Myelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.

Stephan Hutter (S)

MLL Munich Leukemia Laboratory, Munich, Germany.

Thomas La Framboise (T)

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.

Leonor Arenillas (L)

Laboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar and GRETNHE, Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.

Manja Meggendorfer (M)

MLL Munich Leukemia Laboratory, Munich, Germany.

Tomas Radivoyevitch (T)

Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Blanca Xicoy (B)

Hematology Service, Institut Català d'Oncologia (ICO)-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain.

Andrea Pellagatti (A)

Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, United Kingdom.

Claudia Haferlach (C)

MLL Munich Leukemia Laboratory, Munich, Germany.

Jacqueline Boultwood (J)

Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, United Kingdom.

Wolfgang Kern (W)

MLL Munich Leukemia Laboratory, Munich, Germany.

Valeria Visconte (V)

Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Mikkael Sekeres (M)

Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

John Barnard (J)

Department of Quantitative Health Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.

Torsten Haferlach (T)

MLL Munich Leukemia Laboratory, Munich, Germany.

Francesc Solé (F)

Myelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.

Jaroslaw P Maciejewski (JP)

Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: maciejj@ccf.org.

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