Richter’s transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA ( Max gene associated ), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1 / Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 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 Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

中文翻译：

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MGA 缺失通过调节线粒体 OXPHOS 导致 Richter 转化


里氏转化 (RT) 是慢性淋巴细胞白血病 (CLL) 发展为侵袭性淋巴瘤的过程。 MGA（Max 基因相关）是一种功能性 MYC 抑制因子，在 CLL 中发生 3% 的突变，在 RT 中发生 36% 的突变。然而，驱动 CLL 转为 RT 的 MGA 缺失的遗传模型和分子机制仍然难以捉摸。我们通过使用 CRISPR-Cas9 在 Sf3b1 / Mdr CLL 模型中敲除 Mga 来建立 RT 小鼠模型，以确定 Mga 在 RT 中的作用。小鼠 RT 细胞表现出线粒体畸变，氧化磷酸化 (OXPHOS) 升高。通过 RNA 测序和功能表征，我们确定 Nme1（核苷二磷酸激酶）为 Mga 靶标，它通过调节 OXPHOS 驱动 RT。鉴于 NME1 也是已知的 MYC 靶标，但没有可靶向化合物，我们发现同时抑制 MYC 和电子传递链复合物 II 可显着延长 RT 小鼠体内的存活时间。我们的结果表明，Mga-Nme1 轴通过调节 OXPHOS 驱动小鼠 CLL 向 RT 的转变，突出了 RT 的潜在治疗途径。