Integrative therapy for leukemia

Abstract

Acute myeloid leukemia (AML) remains a lethal hematologic malignancy because of frequent relapse, chemotherapy resistance, and treatment-related organ injury. Intensive chemotherapy can induce remission, but patients often succumb to relapsed disease. At the same time, chemotherapy-associated cardiotoxicity limits treatment intensity and threatens long-term survivorship. These challenges call for integrative therapies that eliminate leukemia while preserving critical organ function. This dissertation develops an organ-aware framework for leukemia therapy by focusing on the hematopoietic-cardiovascular axis. We identify angiotensin II receptor type 1 (AGTR1) as a shared molecular node linking AML progression and cardiovascular injury. Using patient transcriptomic analyses, primary human AML samples, xenograft models, and genetically engineered mouse AML models, we show that AGTR1 is enriched in AML cells and functionally supports AML development. Genetic deletion or pharmacologic inhibition of AGTR1 reduces leukemic burden, impairs LSC activity, disrupts AML cell-cycle progression, and prolongs survival. Mechanistically, AGTR1 promotes AML stemness and chemoresistance through Notch1 signaling and associated changes in chromatin organization. Importantly, AGTR1 inhibition with losartan sensitizes AML to chemotherapy while protecting against AML- and chemotherapy-induced cardiotoxicity. Together, this work provides proof-of-concept for integrative leukemia therapy that improves anti-leukemic efficacy while preserving patient health.