Liu Xiaoyu, Liu Yu, Rao Qing, Mei Yihan, Xing Haiyan, Gu Runxia, Mou Junli, Chen Manling, Ding Fan, Xie Wanqing, Tang Kejing, Tian Zheng, Wang Min, Qiu Shaowei, Wang Jianxiang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tianjin Institutes of Health Science, Tianjin, China.
Cancer Res. 2024 Dec 16;84(24):4233-4245. doi: 10.1158/0008-5472.CAN-23-3861.
Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSC) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of preleukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating preleukemic clones, in this study, we used a conditional Runx1::Runx1t1 knockin mouse model to evaluate preleukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these preleukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of preleukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis. Significance: Fatty acid metabolism is required for maintenance of preleukemic cells but dispensable for normal hematopoiesis, indicating that dietary lipid deprivation or inhibiting fatty acid uptake may serve as potential strategies to prevent leukemogenesis.
代谢在维持正常造血干细胞（HSC）以及白血病发展过程中发挥关键作用。更好地了解白血病前期细胞的代谢特征和依赖性，有助于确定预防白血病转化的潜在治疗靶点。由于急性髓系白血病中最常见的融合蛋白之一AML1-ETO由RUNX1::RUNX1T1融合基因编码，能够产生白血病前期克隆，在本研究中，我们使用条件性Runx1::Runx1t1敲入小鼠模型来评估白血病前期细胞的代谢。AML1-ETO的表达导致造血重建受损和自我更新能力增强。这些白血病前期细胞中的氧化磷酸化和糖酵解显著降低，同时造血干细胞静止增加，细胞周期减少。此外，表达AML1-ETO的造血干细胞通过代谢通量对脂肪酸的需求增加。通过使用CRISPR/Cas9进行靶向缺失导致饮食性脂质剥夺或脂肪酸转运蛋白FATP3缺失，部分恢复了分化。这些发现揭示了白血病前期细胞独特的代谢特征，并提出FATP3作为破坏白血病发生的潜在靶点。意义：脂肪酸代谢是维持白血病前期细胞所必需的，但对正常造血并非必需，这表明饮食性脂质剥夺或抑制脂肪酸摄取可能是预防白血病发生的潜在策略。
