RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells
RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells
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DOI：
10.1016/j.ccell.2016.06.002
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发表时间：
2016-07-11
期刊：
影响因子：
50.3
通讯作者：
Jost, Philipp J.
中科院分区：
文献类型：
--
作者：
Hoeckendorf, Ulrike;Yabal, Monica;Jost, Philipp J.
由于急性髓性白血病（AML）的特征在于造血分化和细胞死亡的阻断，我们研究了AML发展中的RIPK 3信号传导。Ripk 3的遗传缺失通过增强白血病起始细胞（LIC）的积累将小鼠FLT 3-ITD驱动的骨髓增殖转化为明显的AML。失败的炎性小体激活和肿瘤坏死因子受体介导的细胞死亡导致LIC的这种积累，例如在Il 1 r1（-/-）、Pycard（-/-）和Tnfr 1/2（-/-）小鼠中加速白血病发作。RIPK 3信号部分由混合谱系激酶结构域样介导。原发性AML患者队列中RIPK 3的显著降低支持了RIPK 3抑制、白细胞介素-1 β释放失败和细胞死亡阻断之间的这种联系。我们的数据将RIPK 3和炎性小体确定为AML中的关键肿瘤抑制因子。
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-1 beta 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.