Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1

Background and Aims Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets.Methods Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors.Results In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1 alpha was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1 alpha neutralizing antibody could improve cardiac functions in AML mice after DNR treatment.Conclusions This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1 alpha neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients. Structured Graphical Abstract In the AML patient, DNR-based chemotherapy causes heart dysfunction and cardiac metabolic disturbance. In the AML mice, cardiac energy metabolism is compromised after DNR treatment, and this process is mediated by IL-1 alpha released from necrotic AML cells. IL-1 alpha combined with IL1R1 in the heart results in the activation of NF-kappa B signalling pathway. This further inhibits myocardial PGC-1 alpha expression, which induces metabolic remodelling and leads to cardiac energy shortages. DNR, daunorubicin; AML, acute myeloid leukaemia; IL-1 alpha, interleukin 1 alpha; IL1R1, interleukin-1 receptor type 1; NF-kappa B, nuclear factor kappa B; PGC-1 alpha, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; ATP, adenosine triphosphate.