Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.
Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.
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DOI：
10.1016/j.celrep.2017.03.018
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发表时间：
2017-03-28
期刊：
影响因子：
8.8
通讯作者：
Agarwal A
中科院分区：
文献类型：
--
作者：
Carey A;Edwards DK 5th;Eide CA;Newell L;Traer E;Medeiros BC;Pollyea DA;Deininger MW;Collins RH;Tyner JW;Druker BJ;Bagby GC;McWeeney SK;Agarwal A
骨髓微环境分泌蛋白在急性髓性白血病（AML）中起关键作用。通过对94种细胞因子的体外功能筛选，我们发现促炎细胞因子白细胞介素-1 （IL-1）在67%的AML患者中引起髓系祖细胞的深度扩增，同时抑制正常祖细胞的生长。AML患者IL-1β和IL-1受体水平升高，IL-1受体的沉默导致克隆性和体内疾病进展的显著抑制。IL-1通过增强p38MAPK磷酸化，促进其他多种生长因子和炎症因子的分泌，从而促进AML细胞生长。使用p38MAPK抑制剂治疗可逆转这些作用，并使正常CD34+细胞从il -1介导的生长抑制中恢复过来。这些结果强调了体外功能筛选对于识别遗传异质性恶性肿瘤中常见和可操作的外在途径的重要性，并为AML中IL-1/IL1R1/p38MAPK途径靶向治疗的临床开发提供了动力。
Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ~67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.
急性粒细胞性白血病细胞中白介素1β的自分泌刺激。
影响因子：
15.3
作者：
Sakai, K;Hattori, T;Matsuoka, M;Asou, N;Yamamoto, S;Sagawa, K;Takatsuki, K
通讯作者：
Takatsuki, K