Cancer Research Institute, Beth Israel Deaconess Cancer Center; Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Cell Res. 2019 Jun;29(6):446-459. doi: 10.1038/s41422-019-0162-7. Epub 2019 Apr 25.
Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.
虽然针对疗法在人类白血病中已被证明是有效甚至可以治愈的，但往往会随之产生耐药性。在大约 20%的人类 AML 中存在 IDH 酶的突变，目前已有针对这些突变的靶向治疗正在进行临床试验。在这里，我们描述了白血病从依赖突变型 IDH2（mIDH2）到不依赖 mIDH2 的演变过程，确定了 mIDH2 白血病在从早期到晚期的进化和进展过程中保留的关键可靶向弱点。从机制上讲，我们发现 mIDH2 白血病在两个不同水平上具有不稳定性和脆弱性。一方面，尽管 1 碳代谢和谷胱甘肽水平增加，但它们仍表现出氧化和遗传毒性应激。另一方面，尽管由于 PIN1 水平增加导致 ATRA 信号转导受到抑制，但 mIDH2 白血病显示 LSD1 抑制和全反式视黄酸（ATRA）敏感性的转录特征。尽管由于 PIN1 水平增加导致 ATRA 信号转导受到抑制，但 mIDH2 白血病显示 LSD1 抑制和全反式视黄酸（ATRA）敏感性的转录特征。尽管由于 PIN1 水平增加导致 ATRA 信号转导受到抑制，但 mIDH2 白血病显示 LSD1 抑制和全反式视黄酸（ATRA）敏感性的转录特征。我们进一步将 GSH/ROS 和 PIN1/LSD1 确定为白血病维持的关键节点，将 ATRA 和三氧化二砷（ATO）的联合作为靶向这些脆弱性的关键治疗方式。引人注目的是，我们证明 ATRA 和 ATO 的联合在多种小鼠和人类 mIDH1/2 白血病模型中是一种强有力的协同有效治疗方法。因此，我们的研究结果为通过靶向 APL 样联合治疗治疗相当一部分人类 AML 铺平了道路。
