14-3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells
14-3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells
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DOI：
10.1182/blood-2006-12-065615
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Chen, Jing
中科院分区：
文献类型：
--
作者：
Dong, Shaozhong;Kang, Sumin;Chen, Jing
人类 8p11 干细胞白血病/淋巴瘤综合征通常表现为骨髓增殖性疾病 (MPD)，并发展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-FGFRi 融合酪氨酸激酶的表达，该激酶在造血转化中发挥致病作用。我们发现 ZNF198-FGFR1 激活 AKT 和丝裂原激活蛋白激酶 (MAPK) 促生存信号通路，导致 AKT 靶标 FOX03a 在 T32 处和 BAD 在 S112 处的磷酸化分别升高。这些磷酸化残基随后将促凋亡的 FOX03a 和 BAD 隔离到 14-3-3 以防止细胞凋亡。我们使用基于肽的 14-3-3 竞争性拮抗剂 R18 来破坏 14-3-3-配体缔合。与对照细胞相比，R18 的表达有效诱导 ZNF198-FGFR1 转化的造血 Ba/F3 细胞凋亡。此外，纯化的重组转录反式激活因子 (TAT) 缀合的 R18 蛋白有效转导到人白血病细胞中，并在表达 FGFR1OP2-FGFR1 融合酪氨酸激酶的 KG-1a 细胞中诱导显着的细胞凋亡，但在对照 HL-60 和 Jurkat T 细胞中则不然。令人惊讶的是，R18 只能解离 FOX03a，但不能解离 14-3-3 结合的 BAD，并部分通过释放和重新激活 FOX03a 来诱导细胞凋亡。我们的研究结果表明，14-3-3 在 FGFR1 融合转化的造血细胞中整合了促存活信号。破坏 14-3-3-配体结合可能是治疗 8p11 干细胞 MPD 的有效治疗策略。
Human 8p11 stem cell leukemia/lymphoma syndrome usually presents 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-FGFRi fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOX03a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOX03a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1 a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOX03a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOX03a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.