缺失通过调节线粒体 OXPHOS 导致 Richter 转化。

deletion leads to Richter's transformation by modulating mitochondrial OXPHOS.

机构信息

Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, CA 91016, USA.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.

出版信息

Sci Transl Med. 2024 Jul 31;16(758):eadg7915. doi: 10.1126/scitranslmed.adg7915.

DOI:10.1126/scitranslmed.adg7915

PMID:39083585

Abstract

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. (), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of in the / CLL model using CRISPR-Cas9 to determine the role of in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified (nucleoside diphosphate kinase) as an target, which drives RT by modulating OXPHOS. Given that is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

摘要

里希特转化（RT）是慢性淋巴细胞白血病（CLL）向侵袭性淋巴瘤的进展。（）是一种功能性 MYC 抑制剂，在 CLL 中突变率为 3%，在 RT 中突变率为 36%。然而，导致 CLL 向 RT 转化的缺失的遗传模型和分子机制仍不清楚。我们使用 CRISPR-Cas9 在 / CLL 模型中敲除，建立了 RT 小鼠模型，以确定在 RT 中的作用。小鼠 RT 细胞表现出线粒体异常，氧化磷酸化（OXPHOS）升高。通过 RNA 测序和功能表征，我们确定（核苷二磷酸激酶）是的靶点，通过调节 OXPHOS 驱动 RT。鉴于也是已知的 MYC 靶点，没有可靶向的化合物，我们发现同时抑制 MYC 和电子传递链复合物 II 可显著延长 RT 小鼠体内的存活时间。我们的结果表明，轴通过调节 OXPHOS 驱动小鼠 CLL 向 RT 转化，突出了 RT 的潜在治疗途径。