Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies
Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies
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DOI：
10.1002/cbf.3869
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发表时间：
2023-10
影响因子：
3.6
通讯作者：
Xiaohui Shen;Peiyuan Dong;Jingjing Kong;Nannan Sun;Fang Wang;Lina Sang;Yan Xu;Mengmeng Zhang;Xiaoli Chen;Rongqun Guo;Shuya Wang;Quande Lin;Zhongxing Jiang;Shan Xu;Congli Zhang;Zhilei Bian;Weimin Wang;Rongqun Guo
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文献类型：
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作者：
Xiaohui Shen;Peiyuan Dong;Jingjing Kong;Nannan Sun;Fang Wang;Lina Sang;Yan Xu;Mengmeng Zhang;Xiaoli Chen;Rongqun Guo;Shuya Wang;Quande Lin;Zhongxing Jiang;Shan Xu;Congli Zhang;Zhilei Bian;Weimin Wang;Rongqun Guo
恶性血液病是最常见的造血疾病，也是一个主要的公共卫生问题。然而，由于突变和多种克隆进化模式之间复杂的相互作用，髓系肿瘤的机制仍然未知，这一点得到了体细胞衍生组学数据分析的证明。几种单细胞组学技术已被用于表征血液系统恶性肿瘤的等级和改变的免疫微环境。血液学恶性肿瘤的综合单细胞图谱为个性化组合靶向治疗提供了新的机会，避免了不必要的化学毒性。在本研究中，我们通过将单细胞RNA测序（scRNA - seq）与急性髓系白血病的靶向致癌基因面板结合进行转录组测序，克服了scRNA - seq在检测致癌突变方面的局限性。在每位患者的骨髓（BM）样本中，确定了每种细胞类型中致瘤性IDH1、IDH2和KRAS突变的分布。我们的研究结果表明，铁凋亡和代谢重编程参与了致癌突变携带细胞的肿瘤发生和化疗耐药。通过IDH1， IDH2和KRAS突变的生物学进展阻止了造血成熟。我们的研究结果为在临床环境中使用原代骨髓细胞进行个性化治疗提供了依据。
Hematologic malignancies are the most common hematopoietic diseases and a major public health concern. However, the mechanisms underlying myeloid tumors remain unknown owing to the intricate interplay between mutations and diverse clonal evolution patterns, as evidenced by the analysis of bulk cell‐derived omics data. Several single‐cell omics techniques have been used to characterize the hierarchies and altered immune microenvironments of hematologic malignancies. The comprehensive single‐cell atlas of hematologic malignancies provides novel opportunities for personalized combinatorial targeted treatments, avoiding unwanted chemo‐toxicity. In the present study, we performed transcriptome sequencing by combining single‐cell RNA sequencing (scRNA‐seq) with a targeted oncogenic gene panel for acute myeloid leukemia, overcoming the limitations of scRNA‐seq in detecting oncogenic mutations. The distribution of oncogenic IDH1, IDH2, and KRAS mutations in each cell type was identified in the bone marrow (BM) samples of each patient. Our findings suggest that ferroptosis and metabolic reprogramming are involved in the tumorigenesis and chemotherapy resistance of oncogenic mutation‐carrying cells. Biological progression via IDH1, IDH2, and KRAS mutations arrests hematopoietic maturation. Our study findings provide a rationale for using primary BM cells for personalized treatment in clinical settings.