RIPK3 通过促进白血病起始细胞的死亡和分化来限制髓性白血病发生。

RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells.

机构信息

III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.

Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), 81377 München, Germany.

出版信息

Cancer Cell. 2016 Jul 11;30(1):75-91. doi: 10.1016/j.ccell.2016.06.002.

DOI:10.1016/j.ccell.2016.06.002

PMID:27411587

Abstract

Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1(-/-), Pycard(-/-), and Tnfr1/2(-/-) mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.

摘要

由于急性髓细胞白血病（AML）的特征是造血分化和细胞死亡受阻，我们研究了 RIPK3 信号在 AML 发展中的作用。Ripk3 的基因缺失通过增强白血病起始细胞（LIC）的积累，将小鼠 FLT3-ITD 驱动的骨髓增生转化为明显的 AML。肿瘤坏死因子受体介导的未成熟的炎性小体激活和细胞死亡导致 LIC 的积累，这表现在 Il1r1(-/-)、Pycard(-/-)和 Tnfr1/2(-/-)小鼠中白血病发病加速。RIPK3 信号部分由混合谱系激酶结构域样蛋白介导。这种抑制 RIPK3、白细胞介素-1β释放失败和阻止细胞死亡之间的联系得到了主要 AML 患者队列中 RIPK3 显著减少的支持。我们的数据表明，RIPK3 和炎性小体是 AML 的关键肿瘤抑制因子。