Neuman Hadas, Arrouasse Jessica, Benjamini Ohad, Mehr Ramit, Kedmi Meirav
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.
Front Oncol. 2023 Mar 16;13:1115361. doi: 10.3389/fonc.2023.1115361. eCollection 2023.
Chronic 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.
Here, 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.
CLL 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.
Overall, 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.
慢性淋巴细胞白血病（CLL）是最常见的成人白血病，占所有成人白血病的30 - 40%。可以使用突变谱系树来研究肿瘤中免疫球蛋白重链可变区（IgHV）基因发生突变的B淋巴细胞CLL克隆（M-CLL）的动态变化。
在此，我们对M-CLL克隆中的体细胞超突变（SHM）和选择进行了基于谱系树的分析，将15例CLL患者的优势（可能为恶性）克隆与其非优势（可能为正常）B细胞克隆以及健康对照库的克隆进行比较。这种分析类型此前从未在CLL研究中发表过，得出了以下新见解。
CLL优势克隆经历或保留了更多改变氨基酸特性（如电荷或亲水性）的替换突变。尽管正如预期的那样，与同一患者的非优势克隆或健康对照中的正常B细胞克隆相比，CLL优势克隆在互补决定区（CDR）对替换突变的选择较弱，对框架区（FWR）中的替换突变的选择也较弱，但令人惊讶的是，它们在FWR中仍保留了部分后者的选择。最后，通过机器学习，我们表明即使是CLL患者中的非优势克隆在各种特征上也与健康对照克隆不同，最显著的是它们具有更高比例的转换突变表达。
总体而言，CLL的特征似乎是作用于B细胞克隆的选择力显著松弛，但并非完全丧失，并且可能还存在SHM机制的变化。
