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选择性抑制HDACIIA类作为KMT2A重组急性淋巴细胞白血病的治疗干预

Tamara C A I Verbeek¹, Kirsten S Vrenken¹, Susan T C J M Arentsen-Peters¹

¹Princess Máxima Center, Utrecht, The Netherlands.

Communications biology

|October 3, 2024

概括

向特定的基因组脱乙酶 (HDAC) IIA 类异型显示出对KMT2A重组的急性淋巴细胞白血病 (ALL) 的承诺. 然而,目前的抑制剂在体内缺乏有效性,需要开发更强效的药物.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

经KMT2A重组的急性淋巴细胞白血病 (ALL) 呈现出表观遗传失调.
素脱乙酶 (HDAC) 抑制是KMT2A重组ALL的潜在治疗策略.
广谱HDAC抑制剂会导致毒性,强调需要针对异构体的特定向.

研究的目的:

调查针对KMT2A重组ALL中的IIA类HDAC异型的治疗潜力.
在临床前模型中评估选择性IIA类HDAC抑制剂的疗效.

主要方法:

在KMT2A重新排列的ALL细胞中,shRNA介导的HDAC4,HDAC5和HDAC7的淘汰.
对HDAC4/5抑制剂LMK-235与ALL细胞系和患者样本进行体外评估.
在KMT2A重新排列的ALL异种移植小鼠模型中对LMK-235,MC1568和TMP195的体内评估.
对LMK-235与venetoclax的联合治疗评估.

主要成果:

降低IIA类HDACs诱导KMT2A重新排列的ALL细胞中的亡和细胞循环停止.
在体外,LMK-235表现出强大的抗白血病活性.
在最大耐受剂量下,IIA类HDAC抑制剂在体内显示出不足的抗白血病作用.
与venetoclax的联合治疗没有显著改善体内生存率.

结论:

第IIA类HDAC异型是KMT2A重组ALL的可行的治疗标.
开发更稳定,更强大的IIA类HDAC抑制剂对于临床转化至关重要.
目前的选择性抑制剂不足以有效地在体内治疗KMT2A重组的ALL.

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