The histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling-RRAGA, MLST8, WDR24 and LAMTOR2-as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.

中文翻译：

---

结合的LSD1和mTORC1抑制作用在MLL易位的急性髓性白血病中的临床前活性。

组蛋白脱甲基酶赖氨酸特异性脱甲基酶1（LSD1或KDM1A）已成为急性髓细胞性白血病（AML）的候选治疗靶点。脯氨酰环丙胺衍生物抑制剂会引起克隆形成活性的丧失并促进分化，特别是在MLL易位的AML分子亚型中。在AML中，联合使用药物通常可提供出色的临床活性。为了鉴定与LSD1协作以维持白血病表型的基因和细胞途径，并且可以通过联合疗法靶向该基因和细胞途径，我们进行了全基因组CRISPR-Cas9缺失筛选。我们确定了mTORC1信号转导-RRAGA，MLST8，WDR24和LAMTOR2的氨基酸传感臂的多个组件，作为对LSD1抑制的细胞敏化剂。降低mTORC1组分或mTORC1的药理抑制作用，结合LSD1抑制作用，可在体外和体内增强细胞系和原代细胞设置的分化，并在模型化的最小残留疾病设置下显着降低克隆性原代人AML细胞的频率。观察到与末端单核细胞谱系分化相关的一组转录因子基因的协同上调。因此，双重抑制mTORC1和LSD1代表了一种增强MLL易位AML分化的候选组合方法，该方法可在早期临床试验中进行评估。观察到与末端单核细胞谱系分化相关的一组转录因子基因的协同上调。因此，双重抑制mTORC1和LSD1代表了一种增强MLL易位AML分化的候选组合方法，该方法可在早期临床试验中进行评估。观察到与末端单核细胞谱系分化相关的一组转录因子基因的协同上调。因此，双重抑制mTORC1和LSD1代表了一种增强MLL易位AML分化的候选组合方法，该方法可在早期临床试验中进行评估。