Mues Marsilius, Roose Jeroen P
a Department of Anatomy , University of California San Francisco , San Francisco , CA , USA.
Small GTPases. 2017 Jan 2;8(1):20-25. doi: 10.1080/21541248.2016.1187323. Epub 2016 May 9.
T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive bone marrow cancer in children and adults, and chemotherapy often fails for relapsing patients. Molecularly targeted therapy is hindered by heterogeneity in T-ALL and mechanistic details of the affected pathways in T-ALL are needed. Deregulation of Ras signals is common in T-ALL. Ras is genetically mutated to a constitutively active form in about 15% of all haematopoietic malignancies, but there is a range of other ways to augment signaling through the Ras pathway. Several groups including our own uncovered that RasGRP1 overexpression leads to T-ALL in mouse models and in pediatric T-ALL patients, and we reported that this Ras guanine nucleotide exchange factor, RasGRP1, cooperates with cytokines to drive leukemogenesis. In our recent study by Ksionda et al. we analyzed the molecular details of cytokine receptor-RasGRP1-Ras signals in T-ALL and compared these to signals from mutated Ras alleles, which yielded several surprising results. Examples are the striking differences in flux through the RasGDP/RasGTP cycle in distinct T-ALL or unexpected differences in wiring of the Ras signaling pathway between T-ALL and normal developing T cells, which we will discuss here.
T细胞急性淋巴细胞白血病/淋巴瘤（T-ALL）是一种侵袭性的儿童和成人骨髓癌，化疗对复发患者往往无效。T-ALL的异质性阻碍了分子靶向治疗，因此需要了解T-ALL中受影响信号通路的机制细节。Ras信号失调在T-ALL中很常见。在所有造血系统恶性肿瘤中，约15%的Ras基因发生突变，转变为组成型活性形式，但还有一系列其他方式可增强通过Ras途径的信号传导。包括我们自己在内的几个研究小组发现，RasGRP1过表达在小鼠模型和小儿T-ALL患者中会导致T-ALL，并且我们报道这种Ras鸟嘌呤核苷酸交换因子RasGRP1与细胞因子协同作用驱动白血病发生。在Ksionda等人最近的研究中，我们分析了T-ALL中细胞因子受体-RasGRP1-Ras信号的分子细节，并将其与来自突变Ras等位基因的信号进行比较，得出了几个惊人的结果。例如，不同T-ALL中RasGDP/RasGTP循环的通量存在显著差异，或者T-ALL与正常发育的T细胞之间Ras信号通路的连接存在意外差异，我们将在此处进行讨论。
