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)-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.

中文翻译：

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阻断IL-1α挽救急性髓系白血病化疗期间的心功能不全

背景和目的 急性髓系白血病 (AML) 患者在基于柔红霉素 (DNR) 的化疗过程中会遭受严重的心肌损伤，并且心脏死亡的风险很高。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发挥重要作用，但这尚未得到证实。本研究旨在确定其潜在机制并探索潜在的治疗靶点。方法 在基于 DNR 的化疗后从 AML 患者身上采集心脏组织，并进行单核 RNA 测序。使用正电子发射断层扫描、磁共振成像和稳定同位素示踪代谢组学评估 DNR 治疗后 AML 小鼠的心脏代谢和功能。 DNR 治疗后对 AML 小鼠的血浆细胞因子进行筛选。使用转基因小鼠和细胞系来验证已确定的细胞因子的核心作用并探索其下游效应器。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，DNR 治疗后心脏脂肪酸利用率减弱，导致心脏功能障碍，但在经过类似治疗的无肿瘤小鼠中没有观察到这些表型。此外，肿瘤细胞源性白细胞介素（IL）-1α被确定为导致DNR诱导的心脏功能障碍的主要因素，并且给予抗IL-1α中和抗体可以改善DNR治疗后AML小鼠的心脏功能。结论本研究表明化疗过程中肿瘤细胞和心肌细胞之间的串扰会扰乱心脏能量代谢并损害心脏功能。 IL-1α 中和抗体治疗是减轻 AML 患者化疗引起的心脏毒性的一种有前途的策略。