LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML
LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML
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DOI：
10.1038/s41375-018-0375-7
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发表时间：
2019-06-01
期刊：
影响因子：
11.4
通讯作者：
Berg, Tobias
中科院分区：
文献类型：
--
作者：
Barth, Jessica;Abou-El-Ardat, Khalil;Berg, Tobias
LSD1 已成为治疗急性髓系白血病 (AML) 的一个有前途的表观遗传靶点。我们使用两种基于 Hoxa9/Meis1 (H9M) 或 MN1 逆转录病毒过表达的小鼠 AML 模型来研究 AML 中 LSD1 功能丧失。 Lsd1 的条件性敲除导致具有粒细胞和单核细胞特征的分化，并增加了 ATRA 敏感性，并延长了患有 H9M 驱动的 AML 小鼠的生存期。条件敲除导致重要的骨髓转录因子 GFI1 和 PU.1 调节的多个基因表达增加。其中包括转录因子 GFI1B 和 IRF8。我们还比较了不同不可逆和可逆 LSD1 抑制剂在 AML 中的作用，结果表明只有反苯环丙明衍生物能够诱导分化反应。我们采用无活性突变 LSD1 的条件敲入模型来研究仅干扰 LSD1 酶活性的效果。虽然这足以启动分化，但它并没有导致小鼠的生存获益。因此，我们认为，有效治疗 AML 需要同时靶向 LSD1 的酶促和支架功能。这一发现以及已确定的生物标志物可能与 LSD1 抑制剂治疗 AML 患者相关。
LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study LSD1 loss of function in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features and increased ATRA sensitivity and extended the survival of mice with H9M-driven AML. The conditional knockout led to an increased expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8. We also compared the effect of different irreversible and reversible inhibitors of LSD1 in AML and could show that only tranylcypromine derivatives were capable of inducing a differentiation response. We employed a conditional knock-in model of inactive, mutant LSD1 to study the effect of only interfering with LSD1 enzymatic activity. While this was sufficient to initiate differentiation, it did not result in a survival benefit in mice. Hence, we believe that targeting both enzymatic and scaffolding functions of LSD1 is required to efficiently treat AML. This finding as well as the identified biomarkers may be relevant for the treatment of AML patients with LSD1 inhibitors.