德国癌症研究中心Andreas Trumpp等研究人员合作发现，单细胞多组学分析揭示了，复杂核型急性髓性白血病中的动态克隆演化和可靶向表型。该项研究成果于2024年11月25日在线发表在《自然—遗传学》上。

研究人员将结构变异发现和核小体占据谱图，与单细胞的转录组和免疫表型变化相结合，以研究复杂核型急性髓性白血病（CK-AML）中的肿瘤内异质性（ITH）。研究人员观察到CK-AML患者个体细胞中的复杂结构变异景观，特征为线性和环状断裂–融合–桥循环以及染色体碎裂（chromothripsis）。

研究人员在诊断或救治阶段的CK-AML中识别出三种克隆演化模式（单克隆、线性多克隆和分支多克隆），其中75%的病例具有多个亚克隆，并且这些亚克隆常常显示出持续的核型重塑。

通过使用患者衍生的异种移植模型，研究人员展示了白血病干细胞（LSC）的克隆演化多样性，并进一步解析了亚克隆特异性的药物反应谱，以识别靶向LSC的治疗方案，包括BCL-xL抑制。

在配对的纵向患者样本中，研究人员进一步揭示了基因演化和细胞类型可塑性作为疾病进展的机制。通过解剖CK-AML的动态基因组、表型和功能复杂性，该研究为表征和靶向驱动疾病的LSC提供了临床相关的途径。

研究人员表示，染色体不稳定性是ITH的主要驱动因素以促进肿瘤进展。

附：英文原文

Title: Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype

Author: Lepp, Aino-Maija, Grimes, Karen, Jeong, Hyobin, Huang, Frank Y., Andrades, Alvaro, Waclawiczek, Alexander, Boch, Tobias, Jauch, Anna, Renders, Simon, Stelmach, Patrick, Mller-Tidow, Carsten, Karpova, Darja, Sohn, Markus, Grnschlger, Florian, Hasenfeld, Patrick, Benito Garagorri, Eva, Thiel, Vera, Dolnik, Anna, Rodriguez-Martin, Bernardo, Bullinger, Lars, Mrzek, Krzysztof, Eisfeld, Ann-Kathrin, Krmer, Alwin, Sanders, Ashley D., Korbel, Jan O., Trumpp, Andreas

Issue&Volume: 2024-11-25

Abstract: Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage–fusion–bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug–response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.

DOI: 10.1038/s41588-024-01999-x

Source: https://www.nature.com/articles/s41588-024-01999-x