Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness
Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness
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DOI：
10.1182/blood-2011-08-373159
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发表时间：
2011-12-22
期刊：
影响因子：
20.3
通讯作者：
Gaidano, Gianluca
中科院分区：
文献类型：
--
作者：
Rossi, Davide;Bruscaggin, Alessio;Gaidano, Gianluca
在慢性淋巴细胞白血病（CLL）中发现的遗传病变并不能完全概括该疾病的发病机制和严重并发症（例如化疗难治性）的发展。在研究氟达拉滨难治性 CLL 的编码基因组时，我们观察到 SF3B1 突变（编码剪接因子并代表细胞剪接体的关键成分）在 59 例氟达拉滨难治性病例中的 10 例 (17%) 中复发，其频率显着高于诊断时连续采样的 CLL 队列中观察到的频率 (17/301, 5%; P = .002)。突变是体细胞获得的，通常以错义核苷酸变化为代表，聚集在 SF3B1 蛋白的选定 HEAT 重复序列中，反复靶向 3 个热点（密码子 662、666 和 700），并且预示着不良预后。在氟达拉滨难治性 CLL 中，SF3B1 突变和 TP53 破坏以相互排斥的方式分布 (P = .046)。 SF3B1 突变的鉴定表明剪接调节是 CLL 中具有潜在临床意义的一种新的发病机制。 （血。2011；118(26):6904-6908）
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. (Blood. 2011;118(26):6904-6908)