B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell–like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.

中文翻译：

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B-ALL 中的白血病启动活性需要类干细胞重编程

B 细胞急性淋巴细胞白血病 (B-ALL) 是一种多步骤疾病，其特征是遗传改变的分层获得。然而，原发癌基因如何重新编程定型 B 细胞中的干细胞样特性并导致肿瘤前群体的问题仍不清楚。在这里，我们使用 PAX5::ELN 致癌模型来证明分化阻断、自我更新和白血病前期干细胞 (pre-LSC) 的出现之间的因果关系。我们发现 PAX5::ELN 通过执行 IL7r/JAK-STAT 通路来破坏白血病前期细胞的分化。正如使用 H2B-GFP 模型评估的那样，这种破坏与维持白血病起始活性的稀有且静止的前 LSC 的诱导有关。转录组和染色质可及性数据的整合表明，那些静止的前 LSC 失去了 B 细胞身份并重新激活了不成熟的分子程序，让人想起人类 B-ALL 化疗耐药细胞。最后，我们的转录调控网络揭示了转录因子 EGR1 是控制 PAX5::ELN pre-LSC 以及人类 B-ALL 原始细胞静止/抵抗的有力候选者。