Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies

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. Significance statement The co‐occurrence of mutations in leukemia cells poses challenges in comprehending the occurrence and progression of leukemia, thereby impeding the adoption of personalized therapeutic approaches. By employing transcriptome sequencing that integrates single‐cell RNA sequencing with a targeted oncogenic gene panel, it becomes possible to identify oncogenic mutations at the individual cell level. This approach enhances our comprehension of disease heterogeneity, disease evolution, novel targeted treatment possibilities, and resistance to chemotherapy. Additionally, our investigation revealed a correlation between IDH1/2 and KRAS mutations and the processes of ferroptosis and metabolic reprogramming.