文章：

新型BMI-1抑制剂PTC596下调MCL-1并诱导急性髓系白血病祖细胞发生p53非依赖性线粒体凋亡

The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells

原文发布日期：2017-02-17

DOI: 10.1038/bcj.2017.8

类型: Original Article

开放获取: 是

英文摘要：

Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization. PTC596 induced apoptosis in a p53-independent manner. PTC596 induced apoptosis along with the reduction of MCL-1 and phosphorylated AKT in patient-derived CD34+CD38low/− stem/progenitor cells. Mouse xenograft models demonstrated in vivo anti-leukemia activity of PTC596, which inhibited leukemia cell growth in vivo while sparing normal hematopoietic cells. Our results indicate that PTC596 deserves further evaluation in clinical trials for refractory or relapsed AML patients, especially for those with unfavorable complex karyotype or therapy-related AML that are frequently associated with p53 mutations.

摘要翻译： 

疾病复发是急性髓系白血病（AML）治疗中的主要难题。复发由白血病干细胞驱动，这是一种能够重建疾病的化疗耐药亚群。p53突变型AML患者的复发风险极高。B细胞特异性莫洛尼鼠白血病病毒整合位点1（BMI-1）是AML干细胞自我更新和维持所必需的因子。本研究旨在探讨新型小分子BMI-1抑制剂PTC596对AML细胞的作用。PTC596处理可降低MCL-1表达，并引发一系列符合线粒体凋亡诱导的分子事件：线粒体膜电位丧失、BAX构象改变、caspase-3裂解和磷脂酰丝氨酸外化。PTC596以不依赖p53的方式诱导细胞凋亡。在患者来源的CD34+CD38low/−干细胞/祖细胞中，PTC596通过降低MCL-1和磷酸化AKT水平诱导凋亡。小鼠异种移植模型证实PTC596具有体内抗白血病活性，能在不影响正常造血细胞的情况下抑制体内白血病细胞生长。我们的研究结果表明，PTC596值得在难治性或复发性AML患者的临床试验中进行进一步评估，特别是针对常伴有p53突变的不良复杂核型或治疗相关AML患者。

原文链接：

The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells