The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

组蛋白脱甲基酶LSD1在包括白血病在内的多种肿瘤中均失活，为LSD1抑制剂的临床使用提供了依据。在急性早幼粒细胞白血病（APL）中，药理剂量的视黄酸（RA）会诱导APL细胞分化，从而触发PML-RAR癌基因的降解。APL细胞对LSD1抑制或敲除具有抗性，但靶向LSD1使它们对RA的生理剂量敏感，而不会改变PML-RAR水平，并延长了RA治疗后白血病小鼠的生存期。RA与LSD1抑制（或敲除）的组合在其他非APL急性髓性白血病（AML）细胞中也有效。LSD1的非酶活性对于阻止分化至关重要，而靶向LSD1的RA则释放分化基因表达程序，不严格依赖组蛋白H3K4甲基化的变化。蛋白质组/表基因组/突变研究的整合表明，LSD1抑制剂改变了含有LSD1的复合物向染色质的募集，抑制了LSD1与转录因子GFI1之间的相互作用。