Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia
Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia
复制标题
DOI：
10.1182/blood-2014-06-580480
复制
发表时间：
2015-03-12
期刊：
影响因子：
20.3
通讯作者：
Teachey, David T.
中科院分区：
文献类型：
--
作者：
Maude, Shannon L.;Dolai, Sibasish;Teachey, David T.
早期 T 细胞前体 (ETP) 急性淋巴细胞白血病 (ALL) 是最近描述的 T-ALL 亚型，其特征是独特的免疫表型和基因组谱以及高诱导失败率。细胞因子受体和 Janus 激酶 (JAK)/信号转导子和转录激活子 (STAT) 信号通路的频繁突变使我们推测 ETP-ALL 依赖于 JAK/STAT 信号传导。在这里，我们证明了相对于非 ETP T-ALL 而言，ETP-ALL 母细胞中 JAK/STAT 通路的异常激活。此外，ETP-ALL 表现出 STAT5 对白细胞介素 7 的过度激活，这种效应被 JAK1/2 抑制剂鲁索替尼消除。在体内，鲁索替尼在 6 个患者来源的 ETP-ALL 小鼠异种移植模型中的 6 个中显示出活性，并且在 5 个模型中具有显着的单药疗效。相对于治疗前水平以及与对照相比，鲁索替尼治疗降低了外周原始细胞计数（P
Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P