DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia.
DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia.
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DOI：
10.1038/s41591-018-0082-y
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发表时间：
2018-08
期刊：
影响因子：
82.9
通讯作者：
Bachovchin DA
中科院分区：
文献类型：
--
作者：
Johnson DC;Taabazuing CY;Okondo MC;Chui AJ;Rao SD;Brown FC;Reed C;Peguero E;de Stanchina E;Kentsis A;Bachovchin DA
丝氨酸二肽酶DPP 8和DPP 9（DPP 8/9）的小分子抑制剂诱导小鼠和人单核细胞和巨噬细胞中称为细胞凋亡的裂解形式的细胞死亡。在小鼠骨髓细胞中，Dpp 8/9抑制激活炎性小体传感器Nlrp 1b，其进而激活前半胱天冬酶-1以介导细胞死亡，但DPP 8/9抑制剂诱导的人类骨髓细胞中的细胞凋亡机制尚不清楚。在这里，我们表明，CARD蛋白CARD 8介导的DPP 8/9通道诱导的前半胱天冬酶-1依赖的人骨髓细胞的细胞凋亡。我们进一步表明，DPP 8/9抑制剂在绝大多数人急性髓性白血病（AML）细胞系和原发性AML样品中诱导细胞凋亡，但在许多其他谱系的细胞中不诱导细胞凋亡，并且这些抑制剂在小鼠模型中抑制人AML进展。总的来说，这项工作确定了人类细胞中第一个已知的CARD 8激活剂，并表明小分子DPP 8/9抑制剂对其的激活代表了AML的一种新的潜在治疗策略。
Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced pro-caspase-1 dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the large majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies the first known activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3.8
作者：
Eager RM;Cunningham CC;Senzer NN;Stephenson J Jr;Anthony SP;O'Day SJ;Frenette G;Pavlick AC;Jones B;Uprichard M;Nemunaitis J
通讯作者：
Nemunaitis J
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
8.6
作者：
Taabazuing CY;Okondo MC;Bachovchin DA
通讯作者：
Bachovchin DA
影响因子：
6.1
作者：
Cunningham, Charles Casey
通讯作者：
Cunningham, Charles Casey