The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros
The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros
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DOI：
10.1038/sj.onc.1210945
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发表时间：
2008-05-01
期刊：
影响因子：
8
通讯作者：
Bohlander, S. K.
中科院分区：
文献类型：
--
作者：
Greif, P. A.;Tizazu, B.;Bohlander, S. K.
t(10; 11)（p13; q14）易位导致了CALM和AF10基因的融合。这种易位是急性淋巴细胞白血病、急性髓性白血病和恶性淋巴瘤中唯一的细胞遗传学异常。在小鼠骨髓移植模型中，原代小鼠骨髓细胞中表达CALM/AF10可导致侵袭性白血病的发生。利用酵母双杂交筛选，我们鉴定出淋巴调节因子Ikaros是AF10相互作用蛋白。有趣的是，Ikaros是淋巴细胞正常发育所必需的，在白血病中发现了Ikaros的异常表达。在小鼠模型中，Ikaros显性阴性异构体的表达导致白血病和淋巴瘤。AF10的Ikaros相互作用结构域被定位到AF10的亮氨酸拉链结构域，这是CALM/AF10和MLL/AF10融合蛋白恶性转化所必需的。通过GST拉下和共免疫沉淀证实了AF10与Ikaros的相互作用。在小鼠成纤维细胞中，共表达CALM/AF10而不表达AF10会改变Ikaros的亚细胞定位。AF10降低了Ikaros的转录抑制因子活性。这些结果表明，CALM/AF10可能干扰正常的Ikaros功能，从而阻断CALM/AF10阳性白血病的淋巴细胞分化。
The t(10; 11)(p13; q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. Using a yeast two-hybrid screen, we identified the lymphoid regulator Ikaros as an AF10 interacting protein. Interestingly, Ikaros is required for normal development of lymphocytes, and aberrant expression of Ikaros has been found in leukemia. In a murine model, the expression of a dominant negative isoform of Ikaros causes leukemias and lymphomas. The Ikaros interaction domain of AF10 was mapped to the leucine zipper domain of AF10, which is required for malignant transformation both by the CALM/AF10 and the MLL/AF10 fusion proteins. The interaction between AF10 and Ikaros was confirmed by GST pull down and co-immunoprecipitation. Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias.