文章：

在Eμ-TCL1小鼠模型中，p53非依鲁替尼应答显示对高危CLL的疗效

p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL

原文发布日期：2016-06-10

DOI: 10.1038/bcj.2016.41

类型: Original Article

开放获取: 是

英文摘要：

Deletion of the short-arm of chromosome 17 (17p-) is one of the most critical genetic alterations used in chronic lymphocytic leukemia (CLL) risk stratification. The tumor suppressor TP53 maps to this region, and its loss or mutation accelerates CLL progression, hampers response to chemotherapy and shortens survival. Although florescent in situ hybridization analyses for 17p deletions are routinely performed during clinical diagnoses, p53 mutational status is often unexamined. Given the limited clinical data that exists for frontline treatment of patients with CLL harboring TP53 mutations, there is a need to understand the biology of CLL with TP53 mutations and identify treatment strategies for this subset of patients. Herein, we used a CLL mouse model (Eμ-TCL1) harboring one of the most common TP53 hot-spot mutations observed in CLL (p53R172H, corresponding to p53R175H in humans) to evaluate its impact on disease progression, survival, response to therapy and loss of the remaining wild-type Trp53 allele following ibrutinib treatment. We show that ibrutinib was effective in increasing survival, activating cellular programs outside the p53 pathway and did not place selective pressure on the remaining wild-type Trp53 allele. These data provide evidence that ibrutinib acts as an effective treatment for aggressive forms of CLL with TP53 mutations.

摘要翻译： 

17号染色体短臂缺失（17p-）是慢性淋巴细胞白血病（CLL）风险分层中最关键的遗传学改变之一。肿瘤抑制因子TP53定位于该区域，其缺失或突变会加速CLL进展、削弱化疗反应并缩短生存期。尽管临床诊断中常规通过荧光原位杂交技术检测17p缺失，但p53突变状态常未被分析。鉴于目前针对携带TP53突变的CLL患者一线治疗的临床数据有限，亟需深入理解TP53突变型CLL的生物学特性，并为该亚群患者探寻治疗策略。本研究采用携带CLL中最常见TP53热点突变之一（p53R172H，对应人类p53R175H）的小鼠模型（Eμ-TCL1），评估该突变对疾病进展、生存期、治疗反应以及依鲁替尼治疗后剩余野生型Trp53等位基因丢失的影响。我们发现依鲁替尼能有效延长生存期，激活p53通路外的细胞程序，且未对剩余野生型Trp53等位基因产生选择压力。这些数据证明，依鲁替尼可作为治疗携带TP53突变的侵袭性CLL的有效方案。

原文链接：

p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL