Abstract：
OBJECTIVE: 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)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α 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-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.
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)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α 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-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.
摘要：
目的：急性髓系白血病（AML）患者在以柔红霉素（DNR）为基础的化疗期间会出现严重的心肌损伤，并有很高的心脏死亡风险。肿瘤细胞和心肌细胞之间的串扰可能在化疗相关的心脏毒性中起重要作用。但这还没有得到证明。本研究旨在明确其潜在机制并探索潜在的治疗靶点。
方法：从基于DNR的化疗后的AML患者收集心脏组织，并进行单核RNA测序。通过使用正电子发射断层扫描评估DNR治疗后AML小鼠的心脏代谢和功能，磁共振成像，和稳定同位素追踪代谢组学。在DNR处理后的AML小鼠中筛选血浆细胞因子。使用遗传修饰的小鼠和细胞系来验证所鉴定的细胞因子的中心作用并探索其下游效应物。
结果：在AML患者中，基于DNR的化疗后心脏代谢稳态的破坏与心功能障碍相关.在AML小鼠中，心脏脂肪酸的利用减弱，导致DNR治疗后心功能不全，但在类似治疗的无瘤小鼠中未观察到这些表型。此外，肿瘤细胞来源的白细胞介素(IL)-1α被确定为导致DNR诱导的心功能不全的主要因素,在DNR治疗后,给予抗IL-1α中和抗体可以改善AML小鼠的心功能.
结论：这项研究表明，化疗期间肿瘤细胞和心肌细胞之间的串扰会干扰心脏能量代谢，损害心脏功能。IL-1α中和抗体治疗是缓解AML患者化疗诱导的心脏毒性的有希望的策略。
方法：从基于DNR的化疗后的AML患者收集心脏组织，并进行单核RNA测序。通过使用正电子发射断层扫描评估DNR治疗后AML小鼠的心脏代谢和功能，磁共振成像，和稳定同位素追踪代谢组学。在DNR处理后的AML小鼠中筛选血浆细胞因子。使用遗传修饰的小鼠和细胞系来验证所鉴定的细胞因子的中心作用并探索其下游效应物。
结果：在AML患者中，基于DNR的化疗后心脏代谢稳态的破坏与心功能障碍相关.在AML小鼠中，心脏脂肪酸的利用减弱，导致DNR治疗后心功能不全，但在类似治疗的无瘤小鼠中未观察到这些表型。此外，肿瘤细胞来源的白细胞介素(IL)-1α被确定为导致DNR诱导的心功能不全的主要因素,在DNR治疗后,给予抗IL-1α中和抗体可以改善AML小鼠的心功能.
结论：这项研究表明，化疗期间肿瘤细胞和心肌细胞之间的串扰会干扰心脏能量代谢，损害心脏功能。IL-1α中和抗体治疗是缓解AML患者化疗诱导的心脏毒性的有希望的策略。
