Ishdorj Ganchimeg, Kost Sara E F, Beiggi Sara, Zang Yunli, Gibson Spencer B, Johnston James B
Research Institute of Oncology and Hematology (Formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
Research Institute of Oncology and Hematology (Formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
Leuk Res. 2017 Aug;59:66-74. doi: 10.1016/j.leukres.2017.05.017. Epub 2017 May 29.
The shelterin proteins play important roles in telomere maintenance and genome stability. These proteins have been found to be mutated in many cancers including CLL. Herein, we demonstrate here the presence of a novel spliced isoform of TIN2S in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene. The expressions of spliced TIN2S mRNA varied widely in CLL and there was an inverse relationship between the mRNA levels of full-length TIN2S and the spliced moiety. Small amounts of spliced TIN2S were also observed in normal B cells but not in T cells. Spliced TIN2S appeared dysfunctional, as immunoprecipitation studies showed the typical association of TRF2 and TIN2 in normal lymphocytes but not in CLL cells. Moreover, whereas TRF2 localized to the nucleus in normal lymphocytes, it was present in both nuclei and cytoplasm in CLL cells. The levels of spliced TIN2S increased with age and in 3 of 8 patients increased over time. The presence of the spliced variant failed to be related to telomere length in CLL suggesting other functions for this protein. Further studies are required to determine the etiology and biological significance of this unique spliced TIN2S variant.
端粒保护蛋白在端粒维持和基因组稳定性中发挥重要作用。这些蛋白已被发现在包括慢性淋巴细胞白血病（CLL）在内的许多癌症中发生突变。在此，我们证明在慢性淋巴细胞白血病（CLL）中存在一种新型的TIN2S剪接异构体，其与TIN2基因外显子2的缺失有关。剪接的TIN2S mRNA在CLL中的表达差异很大，并且全长TIN2S的mRNA水平与剪接部分之间存在负相关。在正常B细胞中也观察到少量剪接的TIN2S，但在T细胞中未观察到。剪接的TIN2S似乎功能失调，因为免疫沉淀研究表明TRF2和TIN2在正常淋巴细胞中有典型的结合，但在CLL细胞中没有。此外，虽然TRF2在正常淋巴细胞中定位于细胞核，但在CLL细胞中它同时存在于细胞核和细胞质中。剪接的TIN2S水平随年龄增加，并且在8名患者中有3名随时间增加。剪接变体的存在与CLL中的端粒长度无关这表明该蛋白具有其他功能。需要进一步研究以确定这种独特的剪接TIN2S变体的病因和生物学意义。
