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
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
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.
disease progression, hydropathy index, mutated CLL (M-CLL), negatively charged HCDR3, neutral HCDR3
Rodríguez-Caballero, Arancha
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Fuentes Herrero, Blanca
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Oliva Ariza, Guillermo
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Criado, Ignacio
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Alcoceba, Miguel
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Prieto, Carlos
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Pérez Caro, María
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García-Montero, Andrés C
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González Díaz, Marcos
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Forconi, Francesco
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Sarmento-Ribeiro, Ana Bela
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Almeida, Julia
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Orfao, Alberto
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26 October 2021
Rodríguez-Caballero, Arancha
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Fuentes Herrero, Blanca
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Oliva Ariza, Guillermo
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Criado, Ignacio
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Alcoceba, Miguel
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Prieto, Carlos
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Pérez Caro, María
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García-Montero, Andrés C
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González Díaz, Marcos
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Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Sarmento-Ribeiro, Ana Bela
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Almeida, Julia
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Orfao, Alberto
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Rodríguez-Caballero, Arancha, Fuentes Herrero, Blanca, Oliva Ariza, Guillermo, Criado, Ignacio, Alcoceba, Miguel, Prieto, Carlos, Pérez Caro, María, García-Montero, Andrés C, González Díaz, Marcos, Forconi, Francesco, Sarmento-Ribeiro, Ana Bela, Almeida, Julia and Orfao, Alberto
(2021)
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.
Frontiers in Oncology, 11, [723722].
(doi:10.3389/fonc.2021.723722).
Abstract
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.
Text
fonc-11-723722
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Accepted/In Press date: 5 October 2021
Published date: 26 October 2021
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Funding
This work was supported by the following grants: FS/37-2017, from the Fundación Memoria D. Samuel Solórzano, Universidad de Salamanca; FIS PI17/00399-FEDER, from the Fondo de Investigación Sanitaria of Instituto de Salud Carlos III, Madrid, Spain; 0639_IDIAL_NET_3_E, from cooperative network EP-INTERREG V A España Portugal (POCTEP); and ECRIN-M3, Accelerator Award Full, Cancer Research UK, Fundación Científica de la Asociación Española Contra el Cáncer (AECC), Fondazione AIRC per la Ricerca sul Cancro. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords:
disease progression, hydropathy index, mutated CLL (M-CLL), negatively charged HCDR3, neutral HCDR3
Identifiers
Local EPrints ID: 452929
URI: http://eprints.soton.ac.uk/id/eprint/452929
ISSN: 2234-943X
PURE UUID: b81bca73-ca4c-4ba0-9787-1fdf8da8f542
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Date deposited: 06 Jan 2022 17:51
Last modified: 17 Mar 2024 03:27
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Contributors
Author:
Arancha Rodríguez-Caballero
Author:
Blanca Fuentes Herrero
Author:
Guillermo Oliva Ariza
Author:
Ignacio Criado
Author:
Miguel Alcoceba
Author:
Carlos Prieto
Author:
María Pérez Caro
Author:
Andrés C García-Montero
Author:
Marcos González Díaz
Author:
Ana Bela Sarmento-Ribeiro
Author:
Julia Almeida
Author:
Alberto Orfao
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