Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Molecular Pathology Unit, MGH Research Institute, Charlestown, MA, 02129, USA.
Leukemia. 2022 Jun;36(6):1533-1540. doi: 10.1038/s41375-022-01590-5. Epub 2022 May 17.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性儿科癌症。在广泛的驱动突变中，10%的 T-ALL 患者存在白细胞介素 7 受体α链（IL-7Rα，由 IL7R 编码）的功能获得性突变，这些突变发生在这种疾病的不同分子亚型中。然而，目前仍不清楚 IL-7R 突变激活是否足以转化 T 细胞前体。此外，与 IL7R 合作驱动白血病发生的基因仍未明确定义。在这里，我们证明突变的 IL7R 本身就能够在稳定的转基因斑马鱼中诱导具有长潜伏期的 T-ALL，并且转化与 MYC 转录激活有关。此外，我们发现突变的 IL7R 与 Myc 合作在转基因斑马鱼中诱导早发性 T-ALL，支持这些途径合作驱动白血病发生的模型。共表达突变的 IL7R 和 Myc 的 T-ALL 激活 STAT5 和 AKT 途径，具有较少数量的凋亡细胞，并比单独表达 Myc 的 T-ALL 更快地在移植的斑马鱼中重新形成肿瘤。此外，有限稀释细胞移植实验表明，激活的 IL-7R 信号增加了白血病传播细胞的总体频率。我们的工作强调了突变的 IL7R 和 Myc 在诱导 T-ALL 中的协同作用，并表明突变的 IL7R 富集了白血病传播的潜力。
