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联合抑制LSD1和Menin诱导AML的治疗差异化

María F Carrera Rodríguez¹, Joshua Rico², Manaswini Vijayaraghavan¹

¹Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA.

bioRxiv : the preprint server for biology

|November 26, 2025

概括

通过诱导细胞分化,LSD1和Menin的双抑制显示出治疗急性髓性白血病 (AML) 的前景. 这种组合疗法针对AML扩散和干性的关键驱动因素,为各种AML亚型提供了一种新策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

急性骨髓性白血病 (AML) 是由不受控制的细胞生长和骨髓成熟的失败.
目前对AML的分化疗法在某些亚型中是有效的,但在其他人中是有限的.
目前正在探索LSD1抑制剂用于AML治疗,但作为单一治疗的临床结果不一致.

研究的目的:

确定与LSD1抑制协同作用的新型治疗点,用于AML差异化治疗.
评估LSD1和Menin的双抑制在非APLAML中的疗效.

主要方法:

利用差异化特定的CRISPR屏幕来识别与LSD1抑制的协同目标.
使用AML细胞系,初级患者样本和小鼠模型验证的结果.
研究了双重LSD1和Menin抑制的机制基础.

主要成果:

梅宁被确定为一种与LSD1抑制有协同作用的顶级打击.
在非APL AML模型中,LSD1和Menin的双抑制有效诱导了终端分化.
门因抑制下调了增殖/干基因 (例如,MEIS1),而LSD1抑制上调了亲差异化通路.

结论:

对LSD1和Menin的双抑制代表了AML分化疗法的有希望的策略.
这种组合疗法在具有多种突变的AML模型中有效,包括没有MLL或NPM1突变的AML模型.
这些发现提名双LSD1和Menin抑制作为广泛的非APLAML亚型的潜在治疗方法.

关键词:

在急性髓性白血病中,急性骨髓性白血病细胞命运细胞命运染色是一种染色素.不同化的差异化表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.一个LSD1一个LSD1 梅宁是什么意思梅宁是什么意思

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