Abstract 4140079: Inhibition of AT1R Attenuates AML and Prevents Chemotherapy-induced Cardiotoxicity

Introduction: Patients with acute myeloid leukemia (AML) frequently develop significant cardiac toxicity when receiving chemotherapy with poor prognosis, but the mechanisms remain largely unknown. Our in silico analysis revealed that angiotensin II receptor type 1 (AT1R) is abundantly expressed in AML and significantly increased in the blood of AML patients. It is known that AT1R is associated with the pathogenesis of cardiomyopathy. Hypothesis: We hypothesize that inhibiting AT1R can simultaneously suppress AML development and reduce chemotherapy-induced cardiotoxicity. Methods and Results: Inhibition of AT1R inhibition using specific AT1R inhibitor or AT1R knockout (KO) substantially reduced AML stemness and boosted chemotherapy efficacy for AML. Mechanistically, AT1R regulates γ-secretase activity, which is responsible for Notch1 transcription factor activation. AT1R KO effectively reduced the expressions of Notch1 downstream genes responsible for AML stemness, cell cycle,and proliferation. When Notch1 was re-introduced into AT1R KO AML cells, the expressions of these Notch1 downstream genes were rescued. Additionally, chromatin structure omics (HiC) and epigenetic omics (CUT&RUN)analysis revealed that 3D-chromatin structural and epigenetic alteration of multiple genes were associated with chemotherapy resistance. In fact, human AML patient derived xenograft model showedAT1R inhibition simultaneously boosted chemotherapy for AML while reducingchemotherapy-induced cardiotoxicity. Further mechanistic study demonstrated that the expression of angiotensin-converting enzyme was significantly increased in the cellsurface of AML with increased blood Ang II level in a mouse model, thus, may contributing to chemotherapy-induced cardiac toxicity. Conclusions: Together, these data demonstrated that AT1R-mediated signaling plays a key role in AML development and chemotherapy-induced cardiotoxicity. These findings indicate that the high incidence of cardiomyopathy in AML was increased AT1R-mediated signaling and targeting AT1R signaling could be a novel strategy for simultaneously suppressingleukemia, boosting chemotherapy efficacy, and preventing chemotherapy-inducedcardiotoxicity.