Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q
Summary: 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: He...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422002407 |
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| author | Vera Adema Laura Palomo Wencke Walter Mar Mallo Stephan Hutter Thomas La Framboise Leonor Arenillas Manja Meggendorfer Tomas Radivoyevitch Blanca Xicoy Andrea Pellagatti Claudia Haferlach Jacqueline Boultwood Wolfgang Kern Valeria Visconte Mikkael Sekeres John Barnard Torsten Haferlach Francesc Solé Jaroslaw P. Maciejewski |
| author_facet | Vera Adema Laura Palomo Wencke Walter Mar Mallo Stephan Hutter Thomas La Framboise Leonor Arenillas Manja Meggendorfer Tomas Radivoyevitch Blanca Xicoy Andrea Pellagatti Claudia Haferlach Jacqueline Boultwood Wolfgang Kern Valeria Visconte Mikkael Sekeres John Barnard Torsten Haferlach Francesc Solé Jaroslaw P. Maciejewski |
| author_sort | Vera Adema |
| collection | DOAJ |
| description | Summary: 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. Funding: 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. |
| first_indexed | 2024-04-13T21:12:50Z |
| format | Article |
| id | doaj.art-06bea150e50f4e07b9fd3c89f1ebed7a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-13T21:12:50Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-06bea150e50f4e07b9fd3c89f1ebed7a2022-12-22T02:29:47ZengElsevierEBioMedicine2352-39642022-06-0180104059Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5qVera Adema0Laura Palomo1Wencke Walter2Mar Mallo3Stephan Hutter4Thomas La Framboise5Leonor Arenillas6Manja Meggendorfer7Tomas Radivoyevitch8Blanca Xicoy9Andrea Pellagatti10Claudia Haferlach11Jacqueline Boultwood12Wolfgang Kern13Valeria Visconte14Mikkael Sekeres15John Barnard16Torsten Haferlach17Francesc Solé18Jaroslaw P. Maciejewski19Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USAMyelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, SpainMLL Munich Leukemia Laboratory, Munich, GermanyMyelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, SpainMLL Munich Leukemia Laboratory, Munich, GermanyDepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USALaboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar and GRETNHE, Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, SpainMLL Munich Leukemia Laboratory, Munich, GermanyDepartment of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USAHematology Service, Institut Català d'Oncologia (ICO)-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, SpainBlood 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 KingdomMLL Munich Leukemia Laboratory, Munich, GermanyBlood 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 KingdomMLL Munich Leukemia Laboratory, Munich, GermanyDepartment of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USALeukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USADepartment of Quantitative Health Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USAMLL Munich Leukemia Laboratory, Munich, GermanyMyelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, SpainDepartment of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Corresponding author.Summary: 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. Funding: 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.http://www.sciencedirect.com/science/article/pii/S2352396422002407Myelodysplastic syndromes5q deletionHaploinsufficiencyTP53CSNK1A1 |
| spellingShingle | Vera Adema Laura Palomo Wencke Walter Mar Mallo Stephan Hutter Thomas La Framboise Leonor Arenillas Manja Meggendorfer Tomas Radivoyevitch Blanca Xicoy Andrea Pellagatti Claudia Haferlach Jacqueline Boultwood Wolfgang Kern Valeria Visconte Mikkael Sekeres John Barnard Torsten Haferlach Francesc Solé Jaroslaw P. Maciejewski Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q EBioMedicine Myelodysplastic syndromes 5q deletion Haploinsufficiency TP53 CSNK1A1 |
| title | Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| title_full | Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| title_fullStr | Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| title_full_unstemmed | Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| title_short | Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| title_sort | pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q |
| topic | Myelodysplastic syndromes 5q deletion Haploinsufficiency TP53 CSNK1A1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422002407 |
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