Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia
Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia
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DOI：
10.1182/blood-2016-06-720433
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发表时间：
2017-02-09
期刊：
影响因子：
20.3
通讯作者：
Pitson, Stuart M.
中科院分区：
文献类型：
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作者：
Powell, Jason A.;Lewis, Alexander C.;Pitson, Stuart M.
急性髓系白血病（AML）是一种侵袭性恶性肿瘤，尽管传统化疗和骨髓移植有所改善，但总体生存率仍然很低。鞘氨醇激酶 1 (SPHK1) 产生生物活性脂质 1 磷酸鞘氨醇 (S1P)，并在多种癌症的肿瘤发生、进展和化疗耐药中发挥作用。然而，之前尚未研究过 SPHK1 在原发性 AML 中的作用和靶向。在这里，我们发现 SPHK1 在原发性 AML 患者原始细胞中过度表达并组成型激活，但在正常单核细胞中则不然。随后靶向 SPHK1 在 AML 细胞系、原发性 AML 患者原始细胞和分离的 AML 患者白血病祖细胞/干细胞中诱导 caspase 依赖性细胞死亡，对来自健康捐赠者的正常骨髓 CD34(+) 祖细胞的影响可以忽略不计。此外，对原位 AML 患者来源的异种移植物施用 SPHK1 抑制剂可减轻肿瘤负荷并延长总体生存期，而不影响小鼠造血。 SPHK1 抑制与 S1P 受体 2 的生存信号传导减少有关，导致促生存蛋白 MCL1 选择性下调。随后的分析表明，BH3 模拟物与 SPHK1 抑制或 S1P 受体 2 拮抗作用的组合可引发协同 AML 细胞死亡。这些结果支持了 SPHK1 是治疗 AML 的真正治疗靶点的观点。
Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34(+) progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML.