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首页> 外文期刊>Cell discovery. >NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K–AKT and JAK–STAT3 pathways
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NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K–AKT and JAK–STAT3 pathways

机译：NTRK2激活通过激活PI3K–AKT和JAK–STAT3途径与T-ALL中PTEN缺乏症协同作用

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摘要

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.
机译：PTEN是磷酸肌醇3激酶信号转导通路的负调节剂，在T细胞急性淋巴细胞白血病中很常见，这表明磷酸肌醇3激酶活性在该疾病中的重要性。实际上，磷酸肌醇3-激酶途径的过度活化与疾病的侵袭性，不良的预后和对当前疗法的抗性有关。为了鉴定能够与PTEN缺乏症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性转化筛选。我们发现NTRK2的激活能够在PTEN无效的情况下以IL3独立的方式赋予Ba / F3细胞完整的生长表型。 NTRK2激活通过参与白细胞中的磷酸肌醇3激酶/ AKT和JAK / STAT3途径激活来协同PTEN缺乏症。值得注意的是，药理学抑制作用表明p110α和p110δ是介导PTEN缺陷型白血病细胞中NTRK2激活驱动的磷酸肌醇3-激酶/ AKT信号传导的主要同工型。此外，磷酸肌醇3-激酶和STAT3的联合抑制作用在培养物中和小鼠异种移植物中均显着抑制了PTEN突变的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缺乏症和NTRK2激活的独特结合，以及磷酸肌醇3-激酶和STAT3信号传导的联合药理抑制作用可作为T细胞急性淋巴细胞白血病的有效且持久的治疗策略白血病。

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