Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Blood. 2011 Dec 22;118(26):6904-8. doi: 10.1182/blood-2011-08-373159. Epub 2011 Oct 28.
The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P = .046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL.
在慢性淋巴细胞白血病（CLL）中鉴定的遗传病变并不能完全重现疾病的发病机制和严重并发症的发展，如化疗耐药。在研究氟达拉滨耐药 CLL 的编码基因组时，我们观察到编码剪接因子的 SF3B1 突变在 59 例氟达拉滨耐药病例中的 10 例（17%）中反复出现，频率明显高于在连续 CLL 队列中在诊断时取样（17/301，5%；P=.002）。突变是体细胞获得的，通常表现为错义核苷酸变化，在 SF3B1 蛋白的选定 HEAT 重复中聚集，反复靶向 3 个热点（密码子 662、666 和 700），并具有不良预后预测性。在氟达拉滨耐药的 CLL 中，SF3B1 突变和 TP53 缺失以相互排斥的方式分布（P=.046）。SF3B1 突变的鉴定指出剪接调控是 CLL 中具有潜在临床相关性的新发病机制。
