■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研究具有突变的免疫球蛋白重链可变区(IgHV)基因的B淋巴细胞CLL克隆在其肿瘤(M-CLL)中的动力学。
■这里,我们使用基于谱系树的体细胞超突变(SHM)分析和M-CLL克隆中的选择,比较15个CLL患者的显性(可能是恶性的)克隆与非显性(可能是正常的)B细胞克隆,以及健康控制剧目。这种类型的分析,以前从未在CLL中发表过,产生了以下新颖的见解。
■CLL显性克隆经历-或保留-更多的替代突变,改变氨基酸特性,如电荷或亲水。虽然,正如预期的那样,CLL显性克隆对互补决定区(CDR)的替代突变和对框架区(FWR)的替代突变的选择比相同患者的非显性克隆或健康对照中的正常B细胞克隆更弱。令人惊讶的是,他们在FWR中保留了一些后者的选择。最后,使用机器学习,我们表明,即使非显性克隆在CLL患者不同的健康对照克隆的各种特征,最值得注意的是它们的过渡突变的更高分数的表达。
■总的来说,CLL的特征似乎在于对B细胞克隆起作用的选择力的明显松动-但不是完全丧失。也可能是由于SHM机制的变化。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.