The Hydropathy Index of the HCDR3 Region of the B-Cell Receptor Identifies Two Subgroups of IGHV-Mutated Chronic Lymphocytic Leukemia Patients With Distinct Outcome.

Autor:	Rodríguez-Caballero A; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., Fuentes Herrero B; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., Oliva Ariza G; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., Criado I; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., Alcoceba M; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.; Department of Hematology, University Hospital of Salamanca/Biomedical Research Institute of Salamanca (HUS/IBSAL), Salamanca, Spain., Prieto C; Bioinformatics Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain., Pérez Caro M; Spanish National DNA Bank Carlos III, University of Salamanca, Salamanca, Spain., García-Montero AC; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., González Díaz M; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.; Department of Hematology, University Hospital of Salamanca/Biomedical Research Institute of Salamanca (HUS/IBSAL), Salamanca, Spain., Forconi F; Haematology Oncology Group, School of Cancer Sciences, Cancer Research UK Centre and National Institute for Health Research Experimental Cancer Medicine, University of Southampton, Faculty of Medicine, Southampton, United Kingdom., Sarmento-Ribeiro AB; Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.; Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal., Almeida J; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain., Orfao A; Translational and Clinical Research Program, Cancer Research Center Institute of Cancer Molecular and Cellular Biology (IBMCC), University of Salamanca-The Spanish National Research Council (USAL-CSIC), Department of Medicine and Cytometry Service, Nucleus Research Support Platform from University of Salamanca (NUCLEUS), University of Salamanca, Salamanca, Spain.; CIBERONC Program of Liquid Biopsy, Hematologic Tumors, Centro de Investigación Biomédica en Red de Cáncer CB16/12/00400 and CB16/12/00233 (CIBERONC), Madrid, Spain.; Molecular and Cellular Biology of Hematologic Tumors, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2021 Oct 26; Vol. 11, pp. 723722. Date of Electronic Publication: 2021 Oct 26 (Print Publication: 2021).
DOI:	10.3389/fonc.2021.723722
Abstrakt:	The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and "antigen-experienced" phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations-e.g., del(17p)-together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Rodríguez-Caballero, Fuentes Herrero, Oliva Ariza, Criado, Alcoceba, Prieto, Pérez Caro, García-Montero, González Díaz, Forconi, Sarmento-Ribeiro, Almeida and Orfao.)
Databáze:	MEDLINE
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