解析 TP53 突变慢性淋巴细胞白血病对伊布替尼治疗反应不佳的原因。

Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib.

机构信息

Department of Molecular Medicine, "Sapienza" University, Rome, Italy.

Department of Cellular Biotechnologies and Haematology, "Sapienza" University, Rome, Italy.

出版信息

Br J Haematol. 2019 Feb;184(3):392-396. doi: 10.1111/bjh.15613. Epub 2018 Oct 18.

DOI:10.1111/bjh.15613

PMID:30338509

Abstract

TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53-M CLL patients.

摘要

TP53 突变的慢性淋巴细胞白血病（CLL）患者对伊布替尼的长期反应不佳。我们在此报告，与 TP53 野生型细胞相比，伊布替尼诱导的体外细胞凋亡和增殖抑制在 TP53 突变（TP53-M）CLL 细胞中显著降低。相反，venetoclax 可有效杀伤 TP53-M 细胞。对 TP53-M 细胞的基因表达谱分析显示，B 细胞受体（BCR）相关基因下调，抗凋亡/生存活性相关基因上调，提示 TP53-M 细胞的存活和增殖对 BCR 通路的依赖性降低。这些观察结果进一步支持联合用药治疗 TP53-M CLL 患者。