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慢性淋巴细胞白血病向里氏综合征转化的进化史。

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.

机构信息

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

出版信息

Nat Med. 2023 Jan;29(1):158-169. doi: 10.1038/s41591-022-02113-6. Epub 2023 Jan 9.

DOI:10.1038/s41591-022-02113-6
PMID:36624313
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10155825/
Abstract

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

摘要

Richter 综合征（RS）由慢性淋巴细胞白血病（CLL）引起，是一种从惰性肿瘤发展而来的侵袭性恶性肿瘤。为了解释这种转化的遗传基础，我们对 52 例 RS 患者的 CLL-RS 细胞混合物进行了计算去卷积，评估了配对的 CLL-RS 全外显子组测序数据。我们发现了 RS 特异性的体细胞驱动突变（包括 IRF2BP2、SRSF1、B2M、DNMT3A 和 CCND3），除了 del(9p21)(CDKN2A/B) 之外还存在复发性拷贝数改变、全基因组复制和染色体重排，这些在 45 例独立的 RS 病例和一组外部 RS 全基因组中得到了证实。通过无监督聚类，克隆相关的 RS 与弥漫性大 B 细胞淋巴瘤有很大的区别。我们区分了 RS 与 CLL 中失调的途径，并在单细胞分辨率下检测到转化的克隆进化，确定了中间细胞状态。我们的研究定义了不同的 RS 分子亚型，并强调了游离 DNA 分析作为早期诊断和监测的潜在工具。

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