Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
Leuk Lymphoma. 2013 Jul;54(7):1364-6. doi: 10.3109/10428194.2012.742528. Epub 2013 Jan 10.
Cellular proteins produced via alternative splicing provide neoplastic cells with survival advantage and/or promote neoplastic cell proliferation. Pre-mRNA is spliced by the spliceosome consisting of large complexes of small nuclear RNA (snRNA) and protein subunits. Spliceosome gene mutations were detected in 40-80% of patients with myelodysplastic syndrome (MDS), particularly in those with ringed sideroblasts. Recently, two large whole-genome sequencing studies identified mutations in the spliceosome gene SF3B1 in approximately 10% of patients with chronic lymphocytic leukemia (CLL). Intrigued by these findings, we performed a pathway enrichment analysis and found that, unlike in MDS, in CLL spliceosome mutations exist almost exclusively in SF3B1. Patients with CLL with an SF3B1 gene mutation are characterized by a short progression-free survival and a low 10-year survival rate. Furthermore, the frequency of SF3B1 mutations is significantly higher in chemotherapy treated than in untreated patients with CLL, suggesting that chemotherapy induces SF3B1 gene mutations or selects a population of mutated cells. Whether SF3B1 gene mutations have a role in leukemogenesis, either because of altered splicing or other splicing-unrelated functions such as ectopic expression of Homeobox (Hox) genes previously reported in SF3B1+(/-) mice, remains to be determined.
通过可变剪接产生的细胞蛋白为肿瘤细胞提供生存优势和/或促进肿瘤细胞增殖。前体 mRNA 由剪接体剪接而成，剪接体由小核 RNA（snRNA）和蛋白质亚基组成的大型复合物组成。在骨髓增生异常综合征（MDS）患者中，约 40-80%检测到剪接体基因突变，尤其是环形铁幼粒细胞患者。最近，两项全基因组测序研究发现，慢性淋巴细胞白血病（CLL）患者中约有 10%存在剪接体基因 SF3B1 突变。受这些发现的启发，我们进行了通路富集分析，发现与 MDS 不同，在 CLL 中，剪接体突变几乎仅存在于 SF3B1 中。具有 SF3B1 基因突变的 CLL 患者的无进展生存期较短，10 年生存率较低。此外，在化疗治疗的 CLL 患者中 SF3B1 突变的频率明显高于未经治疗的患者，这表明化疗诱导 SF3B1 基因突变或选择了具有突变细胞的群体。SF3B1 基因突变是否在白血病发生中起作用，无论是由于改变的剪接还是其他与剪接无关的功能，如以前在 SF3B1(+/−)小鼠中报道的异位表达同源盒（Hox）基因，仍有待确定。
