Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas
Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas
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DOI：
10.1182/blood-2009-08-239996
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发表时间：
2010-01-21
期刊：
影响因子：
20.3
通讯作者：
Lossos, Izidore S.
中科院分区：
文献类型：
--
作者：
Sarosiek, Kristopher A.;Malumbres, Raquel;Lossos, Izidore S.
白细胞介素-21（IL-21）是IL-2细胞因子家族的成员，对自然杀伤（NK）细胞、T细胞和B细胞具有不同的调节作用。与通常具有免疫刺激作用的其他细胞因子相比，IL-21可以在特定的活化-分化阶段诱导小鼠B细胞凋亡。这种作用可用于治疗B细胞恶性肿瘤。在此，我们报告，弥漫性大B细胞淋巴瘤（DLBCL）细胞系表现出广泛表达的IL-21受体（IL-21 R）和IL-21刺激导致细胞周期停滞和半胱天冬酶依赖性凋亡。IL-21还诱导新生DLBCL原发性肿瘤中的细胞凋亡，但不影响人健康B细胞的活力。此外，IL-21促进携带异种移植DLBCL肿瘤的小鼠的肿瘤消退和存活。这种细胞因子的抗淋巴瘤作用依赖于涉及IL-21激活的信号转导子和转录激活子3（STAT 3）上调c-Myc表达的机制。这种上调促进抗凋亡Bcl-2和Bcl-XL蛋白表达的降低，从而触发细胞死亡。我们的研究结果代表了第一个例子，其中STAT 3-c-Myc信号通路，可以促进生存和肿瘤发生，可以诱导肿瘤细胞凋亡。此外，基于IL-21在体外和动物模型中的效力，我们的研究结果表明，这种细胞因子应在DLBCL的临床研究中进行检查。（血。2010; 115：570-580）
Interleukin-21 (IL-21), a member of the IL-2 cytokine family, has diverse regulatory effects on natural killer (NK), T, and B cells. In contrast to other cytokines that are usually immunostimulatory, IL-21 can induce apoptosis of murine B cells at specific activation-differentiation stages. This effect may be used for treatment of B-cell malignancies. Herein we report that diffuse large B-cell lymphoma (DLBCL) cell lines exhibit widespread expression of the IL-21 receptor (IL-21R) and that IL-21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis. IL-21 also induces apoptosis in de novo DLBCL primary tumors but does not affect viability of human healthy B cells. Furthermore, IL-21 promotes tumor regression and prolongs survival of mice harboring xenograft DLBCL tumors. The antilymphoma effects of this cytokine are dependent on a mechanism involving IL-21 activated signal transducer and activator of transcription 3 (STAT3) up-regulating expression of c-Myc. This up-regulation promotes a decrease in expression of antiapoptotic Bcl-2 and Bcl-XL proteins triggering cell death. Our results represent one of the first examples in which the STAT3-c-Myc signaling pathway, which can promote survival and oncogenesis, can induce apoptosis in neoplastic cells. Moreover, based on IL-21's potency in vitro and in animal models, our findings indicate that this cytokine should be examined in clinical studies of DLBCL. (Blood. 2010; 115: 570-580)