Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors. Mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL, occur at a low rate at CLL presentation and have a minor role in Richter transformation, corroborating the notion that CLL histological shift is molecularly distinct from chemorefractory progression without the Richter transformation.

下一代全外显子组测序揭示了两个新基因，即NOTCH1和SF3B1，它们的突变预示预后不良，并优先与化学难治性慢性淋巴细胞白血病 (CLL) 相关。对 539 例 CLL 病例的分析表明，NOTCH1突变 i) 代表了最常见的癌症基因突变之一；ii) 与携带 12 三体的病例聚集，并且在遗传亚组中往往与TP53破坏相互排斥；iii) 识别与TP53异常相关的生存率低的高危患者；iv) 发挥独立于广泛接受的临床和遗传风险因素的预后作用。的突变SF3B1是一种剪接因子，是剪接体的关键组成部分，经常与氟达拉滨难治性 CLL 相关，在 CLL 呈现时发生率较低，在 Richter 转化中起次要作用，证实了 CLL 组织学转变在分子上不同于没有里氏转化的化学难治性进展。