Hartung Emily E, Singh Kanwaldeep, Berg Tobias
Centre for Discovery in Cancer Research, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Front Oncol. 2023 Mar 10;13:1149754. doi: 10.3389/fonc.2023.1149754. eCollection 2023.
Acute Myeloid Leukemia (AML) is a type of cancer of the blood system that is characterized by an accumulation of immature hematopoietic cells in the bone marrow and blood. Its pathogenesis is characterized by an increase in self-renewal and block in differentiation in hematopoietic stem and progenitor cells. Underlying its pathogenesis is the acquisition of mutations in these cells. As there are many different mutations found in AML that can occur in different combinations the disease is very heterogeneous. There has been some progress in the treatment of AML through the introduction of targeted therapies and a broader application of the stem cell transplantation in its treatment. However, many mutations found in AML are still lacking defined interventions. These are in particular mutations and dysregulation in important myeloid transcription factors and epigenetic regulators that also play a crucial role in normal hematopoietic differentiation. While a direct targeting of the partial loss-of-function or change in function observed in these factors is very difficult to imagine, recent data suggests that the inhibition of LSD1, an important epigenetic regulator, can modulate interactions in the network of myeloid transcription factors and restore differentiation in AML. Interestingly, the impact of LSD1 inhibition in this regard is quite different between normal and malignant hematopoiesis. The effect of LSD1 inhibition involves transcription factors that directly interact with LSD1 such as GFI1 and GFI1B, but also transcription factors that bind to enhancers that are modulated by LSD1 such as PU.1 and C/EBPα as well as transcription factors that are regulated downstream of LSD1 such as IRF8. In this review, we are summarizing the current literature on the impact of LSD1 modulation in normal and malignant hematopoietic cells and the current knowledge how the involved transcription factor networks are altered. We are also exploring how these modulation of transcription factors play into the rational selection of combination partners with LSD1 inhibitors, which is an intense area of clinical investigation.
急性髓系白血病（AML）是一种血液系统癌症，其特征是骨髓和血液中存在未成熟造血细胞的积累。其发病机制的特点是造血干细胞和祖细胞的自我更新增加以及分化受阻。其发病机制的基础是这些细胞中获得了突变。由于在AML中发现了许多不同的突变，这些突变可以以不同的组合出现，因此该疾病具有很大的异质性。通过引入靶向治疗以及在其治疗中更广泛地应用干细胞移植，AML的治疗已经取得了一些进展。然而，在AML中发现的许多突变仍然缺乏明确的干预措施。特别是在重要的髓系转录因子和表观遗传调节因子中的突变和失调，它们在正常造血分化中也起着关键作用。虽然很难想象直接针对这些因子中观察到的部分功能丧失或功能改变进行靶向治疗，但最近的数据表明，抑制重要的表观遗传调节因子LSD1可以调节髓系转录因子网络中的相互作用，并恢复AML中的分化。有趣的是，LSD1抑制在这方面对正常和恶性造血的影响有很大不同。LSD1抑制的作用涉及直接与LSD1相互作用的转录因子，如GFI1和GFI1B，但也涉及与由LSD1调节的增强子结合的转录因子，如PU.1和C/EBPα以及在LSD1下游受调节的转录因子，如IRF8。在这篇综述中，我们总结了关于LSD1调节对正常和恶性造血细胞影响的当前文献，以及目前关于所涉及转录因子网络如何改变的知识。我们还探讨了这些转录因子的调节如何有助于合理选择与LSD1抑制剂联合使用的伙伴药物，这是一个临床研究的热点领域。
