B cell M-CLL clones retain selection against replacement mutations in their immunoglobulin gene framework regions

Frontiers in Oncology

Oncology

Ohad Benjamini¹  Hadas Neuman²  Jessica Arrouasse²  Ramit Mehr²  Meirav Kedmi³ 

[1] Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel;Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel;The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel;Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;

关键词: antibody;    B lymphocytes;    chronic lymphocytic leukemia (CLL);    high-throughput sequencing (HTS);    immunoglobulin (Ig);    lineage trees;    somatic hypermutation (SHM);    machine learning (ML);   

DOI  :  10.3389/fonc.2023.1115361

 received in 2022-12-03, accepted in 2023-03-03,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionChronic lymphocytic leukemia (CLL) is the most common adult leukemia, accounting for 30–40% of all adult leukemias. The dynamics of B-lymphocyte CLL clones with mutated immunoglobulin heavy chain variable region (IgHV) genes in their tumor (M-CLL) can be studied using mutational lineage trees.MethodsHere, we used lineage tree-based analyses of somatic hypermutation (SHM) and selection in M-CLL clones, comparing the dominant (presumably malignant) clones of 15 CLL patients to their non-dominant (presumably normal) B cell clones, and to those of healthy control repertoires. This type of analysis, which was never previously published in CLL, yielded the following novel insights. ResultsCLL dominant clones undergo – or retain – more replacement mutations that alter amino acid properties such as charge or hydropathy. Although, as expected, CLL dominant clones undergo weaker selection for replacement mutations in the complementarity determining regions (CDRs) and against replacement mutations in the framework regions (FWRs) than non-dominant clones in the same patients or normal B cell clones in healthy controls, they surprisingly retain some of the latter selection in their FWRs. Finally, using machine learning, we show that even the non-dominant clones in CLL patients differ from healthy control clones in various features, most notably their expression of higher fractions of transition mutations. DiscussionOverall, CLL seems to be characterized by significant loosening – but not a complete loss – of the selection forces operating on B cell clones, and possibly also by changes in SHM mechanisms.

【 授权许可】

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Copyright © 2023 Neuman, Arrouasse, Benjamini, Mehr and Kedmi