Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; and.
Center for Molecular Medicine and Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
Blood Adv. 2018 Sep 11;2(17):2199-2213. doi: 10.1182/bloodadvances.2018021063.
T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27 and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase Pharmacological inhibition of PIM1 abrogates IL-7-mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R.
T 细胞急性淋巴细胞白血病（T-ALL）构成了 ALL 的侵袭性亚群，是最常见的儿童恶性肿瘤。虽然白细胞介素-7（IL-7）是正常 T 细胞发育所必需的，但它也可以通过激活磷脂酰肌醇 3-激酶/蛋白激酶 B/雷帕霉素靶蛋白信号通路来加速体内 T-ALL 的发展和白血病细胞的存活和增殖。在这里，我们研究了 STAT5 是否也可以介导 IL-7 促进 T-ALL 的作用。我们表明，IL-7 诱导 T-ALL 细胞中 STAT 途径的激活，而 STAT5 失活可防止 IL-7 介导的 T-ALL 细胞活力、生长和增殖。在分子水平上，STAT5 是 IL-7 诱导的 p27 下调和转铁蛋白受体 CD71 上调所必需的。令人惊讶的是，STAT5 抑制并没有显著影响 IL-7 介导的 Bcl-2 上调，这表明与正常 T 细胞相反，STAT5 通过一种不依赖 Bcl-2 的机制促进白血病细胞存活。STAT5 染色质免疫沉淀测序和 RNA 测序揭示了 T-ALL 细胞中 IL-7 驱动的 STAT5 依赖性转录程序的多样性，其中包括通过替代转录失活和致癌丝氨酸/苏氨酸激酶的上调。药理学抑制 PIM1 可消除 IL-7 介导的 T-ALL 细胞增殖，表明涉及使用 PIM 激酶小分子抑制剂的策略可能对依赖 IL-7 受体（IL-7R）信号的大多数白血病具有治疗潜力。总的来说，我们的结果表明，STAT5 通过上调 PIM1 活性，在介导 IL-7/IL-7R 的白血病促进作用方面发挥主要作用。
