Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cell Discov. 2016 Sep 20;2:16030. doi: 10.1038/celldisc.2016.30. eCollection 2016.
Loss of PTEN, a negative regulator of the phosphoinositide 3-kinase signaling pathway, is a frequent event in T-cell acute lymphoblastic leukemia, suggesting the importance of phosphoinositide 3-kinase activity in this disease. Indeed, hyperactivation of the phosphoinositide 3-kinase pathway is associated with the disease aggressiveness, poor prognosis and resistance to current therapies. To identify a molecular pathway capable of cooperating with PTEN deficiency to drive oncogenic transformation of leukocytes, we performed an unbiased transformation screen with a library of tyrosine kinases. We found that activation of NTRK2 is able to confer a full growth phenotype of Ba/F3 cells in an IL3-independent manner in the PTEN-null setting. NTRK2 activation cooperates with PTEN deficiency through engaging both phosphoinositide3-kinase/AKT and JAK/STAT3 pathway activation in leukocytes. Notably, pharmacological inhibition demonstrated that p110α and p110δ are the major isoforms mediating the phosphoinositide 3-kinase/AKT signaling driven by NTRK2 activation in PTEN-deficient leukemia cells. Furthermore, combined inhibition of phosphoinositide 3-kinase and STAT3 significantly suppressed proliferation of PTEN-mutant T-cell acute lymphoblastic leukemia both in culture and in mouse xenografts. Together, our data suggest that a unique conjunction of PTEN deficiency and NTRK2 activation in T-cell acute lymphoblastic leukemia, and combined pharmacologic inhibition of phosphoinositide 3-kinase and STAT3 signaling may serve as an effective and durable therapeutic strategy for T-cell acute lymphoblastic leukemia.
PTEN 的缺失，作为磷酸肌醇 3-激酶信号通路的负调控因子，在 T 细胞急性淋巴细胞白血病中是一个常见事件，提示磷酸肌醇 3-激酶活性在该疾病中的重要性。事实上，磷酸肌醇 3-激酶途径的过度激活与疾病侵袭性、预后不良和对当前治疗的耐药性有关。为了鉴定能够与 PTEN 缺失协同作用以驱动白细胞致癌转化的分子途径，我们使用酪氨酸激酶文库进行了无偏置转化筛选。我们发现，NTRK2 的激活能够在 PTEN 缺失的情况下以 IL3 非依赖性方式赋予 Ba/F3 细胞完全的生长表型。NTRK2 的激活通过在白细胞中同时激活磷酸肌醇 3-激酶/AKT 和 JAK/STAT3 途径与 PTEN 缺失协同作用。值得注意的是，药理学抑制表明 p110α 和 p110δ 是介导 NTRK2 激活驱动的 PTEN 缺陷白血病细胞中磷酸肌醇 3-激酶/AKT 信号的主要同工型。此外，磷酸肌醇 3-激酶和 STAT3 的联合抑制显著抑制了培养物和小鼠异种移植中 PTEN 突变型 T 细胞急性淋巴细胞白血病的增殖。总之，我们的数据表明，T 细胞急性淋巴细胞白血病中 PTEN 缺失和 NTRK2 激活的独特结合，以及磷酸肌醇 3-激酶和 STAT3 信号的联合药物抑制可能是 T 细胞急性淋巴细胞白血病的一种有效和持久的治疗策略。
