Max Planck Institute for Metabolism Research, Cologne, Germany.
Institute for Genetics, University of Cologne, Cologne, Germany.
Blood. 2021 Feb 4;137(5):646-660. doi: 10.1182/blood.2020005734.
Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.
里希特转化（RT）是一种侵袭性淋巴瘤，发生在慢性淋巴细胞白血病（CLL）进展后。转化与 CLL 期涉及 TP53、CDKN2A、MYC 和 NOTCH1 的遗传异常有关；然而，很大一部分 RT 病例缺乏 CLL 期相关事件。在这里，我们报告说，高磷酸化 AKT 水平既存在于携带 TP53 和 NOTCH1 突变的高危 CLL 患者中，也存在于 RT 患者中。在小鼠 Eµ-TCL1 CLL 小鼠模型中，Akt 的遗传过度激活导致 CLL 转化为 RT，生存显著降低，表现出侵袭性淋巴瘤表型。在没有反复突变的情况下，我们确定了介于 CLL 和弥漫性大 B 细胞淋巴瘤之间的基因组异常谱。通过磷酸化蛋白质组/蛋白质组和 Akt 诱导的小鼠 RT 的单细胞转录组谱的多组学评估，揭示了一个 S100 蛋白定义的高度侵袭性淋巴瘤细胞亚群，这些细胞源自 CLL 细胞，通过 T 细胞表达的 Notch 配体激活 Notch 信号。同样，组成性激活的 Notch1 也诱导了小鼠 CLL 的 RT。我们确定 Akt 激活是通过诱导 RT 细胞和微环境 T 细胞之间的 Notch 信号，引发 CLL 向侵袭性淋巴瘤转化的启动子。
