Terry Fox Laboratory/Department of Pathology, BC Cancer Agency, Vancouver, BC, V52 1L3 Canada.
J Exp Med. 2011 Aug 29;208(9):1809-22. doi: 10.1084/jem.20110121. Epub 2011 Aug 1.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K-Akt pathways. Although mutations that activate PI3K-Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.
T 细胞急性淋巴细胞白血病（T-ALL）是一种幼稚 T 细胞的侵袭性癌症，通常表现为 Notch1 和 PI3K-Akt 通路的异常激活。尽管先前已经鉴定出激活 PI3K-Akt 信号的突变，但生长因子依赖性激活的相对贡献尚不清楚。我们在这里表明，胰岛素样生长因子 1 受体（IGF1R）的药物抑制或基因缺失会阻断 T-ALL 细胞的生长和存活，而 IGF1R 信号的适度减弱会损害白血病起始细胞（LIC）的活性，正如在同基因/同源性二级受者中的移植能力所定义的那样。此外，IGF1R 是 Notch1 的靶标，而 Notch1 信号通路需要在 T-ALL 细胞中维持 IGF1R 的高水平表达。这些发现表明 Notch 对 LIC 活性的影响可能部分是通过增强 T-ALL 细胞对环境生长因子的反应性来介导的，为使用 IGF1R 抑制剂来改善初始治疗反应和实现 T-ALL 患者的长期治愈提供了强有力的理由。
