The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells
The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells
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DOI：
10.1038/sj.leu.2403415
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发表时间：
2004-08-01
期刊：
影响因子：
11.4
通讯作者：
Hemenway, CS
中科院分区：
文献类型：
--
作者：
Srinivasan, RS;Nesbit, JB;Hemenway, CS
染色体11 q23带的MLL基因通常参与急性白血病中检测到的相互易位。大量实验表明，所产生的MLL融合基因直接促进白血病的发生。在许多已知的MLL融合伴侣中，AF 4相对常见，特别是在婴儿急性淋巴细胞白血病中。AF 4蛋白与另一个基因AF 9的产物相互作用，AF 9也与急性白血病中的MLL融合。基于对AF 4的AF 9结合结构域的作图研究，我们开发了一种肽，命名为PFWT，其在体外和体内破坏AF 4-AF 9相互作用。我们提供的证据表明，该肽能够抑制表达MLL-AF 4融合基因的t（4;11）染色体易位白血病细胞的增殖。此外，我们表明，这种抑制是通过细胞凋亡介导的。重要的是，该肽不影响造血祖细胞的增殖能力。我们的研究结果表明，AF 4-AF 9蛋白复合物是白血病治疗的一个有前途的新靶点，PFWT肽可能作为药物开发的先导化合物。
The MLL gene at chromosome band 11q23 is commonly involved in reciprocal translocations detected in acute leukemias. A number of experiments show that the resulting MLL fusion genes directly contribute to leukemogenesis. Among the many known MLL fusion partners, AF4 is relatively common, particularly in acute lymphoblastic leukemia in infants. The AF4 protein interacts with the product of another gene, AF9, which is also fused to MLL in acute leukemias. Based on mapping studies of the AF9-binding domain of AF4, we have developed a peptide, designated PFWT, which disrupts the AF4-AF9 interaction in vitro and in vivo. We provide evidence that this peptide is able to inhibit the proliferation of leukemia cells with t(4;11) chromosomal translocations expressing MLL-AF4 fusion genes. Further, we show that this inhibition is mediated through apoptosis. Importantly, the peptide does not affect the proliferative capacity of hematopoietic progenitor cells. Our findings indicate that the AF4-AF9 protein complex is a promising new target for leukemia therapy and that the PFWT peptide may serve as a lead compound for drug development.