Abstract：
Clinical treatment of acute myeloid leukemia (AML) largely relies on intensive chemotherapy. However, the application of chemotherapy is often hindered by cardiotoxicity. Patient sequence data revealed that angiotensin II receptor type 1 (AGTR1) is a shared target between AML and cardiovascular disease (CVD). We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against chemotherapy-induced cardiotoxicity in a human AML cell-transplanted mouse model. These effects were regulated by the AGTR1-Notch1 axis in AML cells and cardiomyocytes from mice. In mouse cardiomyocytes, AGTR1 was hyperactivated by AML and chemotherapy. AML leukemogenesis increased the expression of the angiotensin-converting enzyme and led to increased production of angiotensin II, the ligand of AGTR1, in an MLL-AF9-driven AML mouse model. In this model, the AGTR1-Notch1 axis regulated a variety of genes involved with cell stemness and chemotherapy resistance. AML cell stemness was reduced after Agtr1a deletion in the mouse AML cell transplant model. Mechanistically, Agtr1a deletion decreased γ-secretase formation, which is required for transmembrane Notch1 cleavage and release of the Notch1 intracellular domain into the nucleus. Using multiomics, we identified AGTR1-Notch1 signaling downstream genes and found decreased binding between these gene sequences with Notch1 and chromatin enhancers, as well as increased binding with silencers. These findings describe an AML/CVD association that may be used to improve AML treatment.
摘要：
急性髓系白血病（AML）的临床治疗在很大程度上依赖于强化化疗。然而,化疗的应用通常受到心脏毒性的阻碍。患者序列数据显示，血管紧张素II受体1型（AGTR1）是AML和心血管疾病（CVD）之间的共同靶标。我们发现，在人AML细胞移植小鼠模型中，抑制AGTR1可使AML对化疗敏感，并保护心脏免受化疗诱导的心脏毒性。这些作用在小鼠的AML细胞和心肌细胞中受到AGTR1-Notch1轴的调节。在小鼠心肌细胞中，AGTR1被AML和化疗过度激活。AML白血病的发生增加了血管紧张素转换酶的表达，并导致血管紧张素II的产生增加，AGTR1的配体，在MLL-AF9驱动的AML小鼠模型中。在这个模型中,AGTR1-Notch1轴调节多种与细胞干性和化疗耐药有关的基因。在小鼠AML细胞移植模型中,Agtr1a缺失后AML细胞干性降低。机械上,Agtr1a缺失减少了γ-分泌酶的形成，这是跨膜Notch1裂解和将Notch1胞内结构域释放到细胞核中所需的。使用多元组学，我们鉴定了AGTR1-Notch1信号传导下游基因，并发现这些基因序列与Notch1和染色质增强剂之间的结合减少，以及增加与消音器的结合。这些发现描述了可用于改善AML治疗的AML/CVD关联。
