PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder
PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder
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DOI：
10.1073/pnas.0404438101
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发表时间：
2004-10-05
影响因子：
11.1
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Chen, J;DeAngelo, DJ;Gilliland, DG
人类干细胞白血病-淋巴瘤综合征通常表现为一种骨髓增生性疾病(MPD)，演变为急性髓系白血病和/或淋巴瘤。与t(8；13)(p11；q12)相关的综合征导致ZNF198-成纤维细胞生长因子受体(FGFR)1融合酪氨酸激酶的表达。目前经验性的细胞毒化疗不足以治疗这种疾病。我们假设ZNF198-FGFR1融合的小分子抑制剂将具有治疗效果。我们研究了ZNF198-FGFR1在体外和体内对造血细胞的转化活性。ZNF198-FGFR1在原代小鼠造血细胞中的表达导致了小鼠的骨髓增殖性综合征，这与人类MPD的表型相似。在这些检测中的转化和下游效应分子PLC-伽马、STAT5和磷脂酰肌醇3-激酶/AKT的激活，需要ZNF198的富含脯氨酸的结构域，而不是ZNF198的ZNF结构域。小分子酪氨酸激酶抑制剂PKC412(N-苯甲酰-星形孢子素)能有效抑制ZNF198-FGFR1酪氨酸激酶活性和下游效应通路的激活，抑制ZNF198-FGFR1转化的BA/F3细胞增殖。此外，在ZNF198-FGFR1诱导的MPD小鼠模型中，PKC412的治疗结果在统计学上显著延长了存活时间。部分基于这些数据，PKC412用于t(8；13)(p11；q12)患者，并对器官肿大的进行性骨髓增生性疾病有效。因此，PKC412有可能成为治疗人类干细胞白血病-淋巴瘤综合征的有效药物。
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.