Article Impact Level: HIGH Data Quality: STRONG Summary of Science Translational Medicine, 16(752), eadl5931. https://doi.org/10.1126/scitranslmed.adl5931 Dr. Yi Pan et al.
Points
- Angiotensin II receptor type 1 (AGTR1) has been identified as a common target in acute myeloid leukemia (AML) and cardiovascular disease (CVD), impacting both chemotherapy sensitivity and cardiotoxicity.
- The AGTR1-Notch1 signaling pathway regulates AML cell stemness, chemotherapy resistance, and cardiomyocyte response to chemotherapy.
- In a mouse model with AML cell transplants, hyperactivation of AGTR1 due to AML and chemotherapy was linked to increased angiotensin II production and elevated angiotensin-converting enzyme expression, enhancing chemotherapy-induced cardiotoxicity.
- The AGTR1-Notch1 axis modulates the expression of genes related to cell stemness and chemotherapy resistance, with AGTR1 deletion reducing AML cell stemness by decreasing γ-secretase formation necessary for Notch1 cleavage.
- The study suggests that targeting AGTR1 may improve AML therapy by reducing chemotherapy resistance and cardiotoxicity, offering new therapeutic avenues and insights into gene regulation by the AGTR1-Notch1 signaling pathway.
Summary
Acute myeloid leukemia (AML) treatment traditionally involves intensive chemotherapy, yet the development of cardiotoxicity often limits its efficacy. Analysis of patient sequence data has unveiled angiotensin II receptor type 1 (AGTR1) as a common target in both AML and cardiovascular disease (CVD). This study delves into the impact of AGTR1 inhibition on AML sensitivity to chemotherapy and the mitigation of chemotherapy-induced cardiotoxicity in a human AML cell-transplanted mouse model. The research highlights the pivotal role of the AGTR1-Notch1 axis in regulating these effects within AML cells and cardiomyocytes.
The study demonstrates that hyperactivation of AGTR1 in mouse cardiomyocytes, induced by AML and chemotherapy, is associated with increased angiotensin II production, facilitated by elevated angiotensin-converting enzyme expression in an MLL-AF9-driven AML mouse model. The AGTR1-Notch1 axis modulates the expression of genes linked to cell stemness and chemotherapy resistance in this model. Deletion of Agtr1a in the mouse AML cell transplant model resulted in reduced AML cell stemness, attributed to the decreased formation of γ-secretase, crucial for Notch1 cleavage and subsequent release of the Notch1 intracellular domain.
The findings underscore the intricate interplay between AML and CVD through the AGTR1-Notch1 axis, shedding light on a potential strategy to enhance AML therapy. By elucidating the molecular mechanisms underlying AGTR1-mediated effects on AML sensitivity to chemotherapy and cardiotoxicity, this study provides valuable insights into novel therapeutic avenues for AML treatment. Identifying downstream genes regulated by AGTR1-Notch1 signaling and alterations in gene binding patterns offers a promising foundation for further research to refine AML treatment strategies and address chemotherapy-related cardiotoxicity.
Link to the article: https://www.science.org/doi/10.1126/scitranslmed.adl5931
References Pan, Y., Wang, C., Zhou, W., Shi, Y., Meng, X., Muhammad, Y., Hammer, R. D., Jia, B., Zheng, H., Li, D.-P., Liu, Z., Hildebrandt, G., & Kang, X. (2024). Inhibiting AGTR1 reduces AML burden and protects the heart from cardiotoxicity in mouse models. Science Translational Medicine, 16(752), eadl5931. https://doi.org/10.1126/scitranslmed.adl5931
