Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia
Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia
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DOI：
10.1182/blood-2010-04-277418
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发表时间：
2010-12-23
期刊：
影响因子：
20.3
通讯作者：
Waldmann, Thomas A.
中科院分区：
文献类型：
--
作者：
Chen, Jing;Petrus, Mike;Waldmann, Thomas A.
成人T细胞白血病（ATL）是一种异质性疾病，临床上可分为郁积型、慢性型、淋巴瘤型和急性型。除了不同的临床表现外，ATL的不同阶段具有不同的分子特征。在这里，我们证明，阴燃/慢性ATL外周血单核细胞自发增殖离体细胞因子（白细胞介素-12 [IL-12]/IL-9/IL-15）依赖的方式，而急性型ATL外周血单核细胞不增殖或增殖的细胞因子无关。阴燃/慢性ATL细胞在6天离体培养物中产生IL-2和IL-9。有趣的是，抗IL-2 R-alpha单克隆抗体的添加显著抑制IL-9表达，表明IL-9的最佳表达依赖于这些患者中的IL-2信号传导。为了确定ATL白血病细胞是否会自主增殖，我们从郁积/慢性ATL患者中纯化白血病细胞。单独培养的纯化白血病细胞产生IL-2/IL-9，下游Janus激酶/信号转导和转录激活因子通路被激活。然而，白血病细胞并不能独立增殖，而是需要与自体单核细胞共培养才能诱导增殖。此外，白血病细胞和单核细胞之间的相互作用是接触依赖性的，和主要组织相容性复合物II类表达可能有助于这种相互作用。总之，我们的数据提供的证据表明，有自分泌/旁分泌细胞因子刺激白血病细胞增殖的患者闷烧/慢性ATL，可以有针对性的治疗。（血。2010;116（26）：5948-5956）
Adult T-cell leukemia (ATL), a heterogeneous disease, can be divided into smoldering, chronic, lymphoma, and acute types clinically. In addition to different clinical manifestations, different stages of ATL have different molecular signatures. Here, we demonstrated that smoldering/chronic ATL peripheral blood mononuclear cells spontaneously proliferated ex vivo in a cytokine (interleukin -12 [IL-12]/IL-9/IL-15)-dependent manner, while acute-type ATL peripheral blood mononuclear cells did not proliferate or proliferated independent of cytokines. Smoldering/chronic ATL cells produced IL-2 and IL-9 in 6-day ex vivo cultures. Interestingly, the addition of an anti-IL-2R-alpha monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/IL-9, and the downstream Janus kinase/signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. (Blood. 2010;116(26):5948-5956)