Bayet Manon, Fregona Vincent, Bouttier Mathieu, Rouzier Clémence, Bigot Jérémy, Jamrog Laura, Hebrard Sylvie, Prade Naïs, Lagarde Stéphanie, Didier Christine, Gachet Stéphanie, Passet Marie, Largeaud Laetitia, Pasquet Marlène, Khamlichi Ahmed Amine, Clappier Emmanuelle, Delabesse Eric, Broccardo Cyril, Gerby Bastien
Univ Toulouse, CHU Toulouse, CNRS, INSERM, CRCT, Toulouse, France.
Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France.
Cancer Res. 2025 Aug 1;85(15):2820-2837. doi: 10.1158/0008-5472.CAN-24-1698.
The transcription factor PAX5 is a major target of genetic alterations in human B-cell precursor acute lymphoblastic leukemia (B-ALL). Among the alterations, the P80R mutation affecting the DNA-binding domain represents the most frequent PAX5 point mutation in B-ALL. In contrast to other somatic PAX5 mutations, PAX5P80R defines a distinct B-ALL subtype characterized by a unique transcriptional program. In this study, we aimed to develop a model to elucidate the mechanism by which PAX5P80R perturbs normal B-cell differentiation and the oncogenic relays involved in PAX5P80R-driven malignant progression. A retroviral complementation approach of Pax5-deficient murine fetal liver cells demonstrated at the functional and molecular levels that PAX5P80R failed to rescue definitive B-cell commitment but maintained the repression of T-cell development. Moreover, PAX5P80R eventually led to clonal B-ALL transformation after transplantation through the acquisition of secondary mutations in genes involved in the JAK/STAT and RAS/MAPK pathways. Finally, transcriptomic analyses combined with pharmacologic investigation revealed ectopic activation of HIF2α as a common feature of B-ALL and identified acriflavine as a potent drug against B-ALL. Hence, this study provides a strategy to model the multistep process of B-ALL and sheds light on the biological mechanism by which the PAX5P80R mutation leads to leukemia.
PAX5P80R perturbs normal B-cell development, leads to clonal transformation, and activates HIF2α as an oncogenic relay, providing mechanistic insights that could improve treatment of B-cell acute lymphoblastic leukemia.
转录因子PAX5是人类B细胞前体急性淋巴细胞白血病（B-ALL）基因改变的主要靶点。在这些改变中，影响DNA结合域的P80R突变是B-ALL中最常见的PAX5点突变。与其他体细胞PAX5突变不同，PAX5P80R定义了一种独特的B-ALL亚型，其特征是具有独特的转录程序。在本研究中，我们旨在建立一个模型，以阐明PAX5P80R扰乱正常B细胞分化的机制以及参与PAX5P80R驱动的恶性进展的致癌信号传导途径。对Pax5缺陷型小鼠胎肝细胞的逆转录病毒互补方法在功能和分子水平上表明，PAX5P80R未能挽救确定的B细胞定向分化，但维持了对T细胞发育的抑制。此外，PAX5P80R在移植后最终通过获得JAK/STAT和RAS/MAPK途径相关基因的二次突变导致克隆性B-ALL转化。最后，转录组分析与药理学研究相结合，揭示了HIF2α的异位激活是B-ALL的一个共同特征，并确定吖啶黄是一种有效的抗B-ALL药物。因此，本研究提供了一种对B-ALL多步骤过程进行建模的策略，并阐明了PAX5P80R突变导致白血病的生物学机制。
PAX5P80R扰乱正常B细胞发育，导致克隆转化，并激活HIF2α作为致癌信号传导途径，提供了可能改善B细胞急性淋巴细胞白血病治疗的机制性见解。
