Experimental hematology & oncology · 2026
Single-cell profiling reveals reprogrammed hierarchy and disrupted immune-stromal ecosystem in TP53-mutated AML.
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Qiu Guo, Yin Zhao, Lu Xiaoyue, Xue Rongtao, Tang Shengjiao, Zhou Cuiyan, Huang Xueping, Fan Menglin, Ai Yanjia, Xiang Guangmei, Wang Luting, Yu Sijian, Yu Guopan, Shi Pengcheng, Zhao Ke, Liu Hui, Zhang Yu, Shan Meng, Xuan Li, Xiong Jing, Xu Xi, Liu Qifa, Wang Yu
Аннотация
BACKGROUND: TP53-mutated acute myeloid leukemia (AML) represents one of the most adverse-risk subtypes of AML, yet the mechanisms underlying its resistance and relapse remain poorly defined.
METHODS: We performed single-cell RNA sequencing on bone marrow samples from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type) and systematically analyzed leukemic, immune, and stromal compartments to delineate differentiation trajectories, transcriptional heterogeneity, and microenvironmental remodeling. We also performed in vitro assays to validate ferroptosis resistance, leukemia-T cell dysfunction, and stromal remodeling suggested by the single-cell data.
RESULTS: TP53-mutated AML exhibited a differentiation bias toward granulocyte-monocyte and late myeloid progenitors rather than arrest at the stem cell stage, with enhanced anti-apoptotic and inflammatory programs and a transcriptionally and functionally supported ferroptosis resistance phenotype as a novel hallmark linked to poor prognosis. Functionally, CD8⁺ T cells were predominantly exhausted with an enrichment of dysfunctional subsets and a concomitant reduction of NK cells. B cells showed impaired activation with skewed plasma cell composition, and myeloid cells acquired immunosuppressive features. In the stromal compartment, mesenchymal cells lost hematopoietic and immune-supportive functions and shifted toward osteogenic programs, further reinforcing leukemic survival. We also established an integrated ecosystem score that, together with TP53 mutation burden and mono- versus multi-hit status, captured prognostic heterogeneity and enabled clinical stratification.
CONCLUSIONS: This study provides the first single-cell landscape of de novo TP53-mutated AML, highlighting its reprogrammed leukemic hierarchy and disrupted immune-stromal ecosystem, and offering mechanistic insights and potential therapeutic targets for this high-risk subtype.
METHODS: We performed single-cell RNA sequencing on bone marrow samples from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type) and systematically analyzed leukemic, immune, and stromal compartments to delineate differentiation trajectories, transcriptional heterogeneity, and microenvironmental remodeling. We also performed in vitro assays to validate ferroptosis resistance, leukemia-T cell dysfunction, and stromal remodeling suggested by the single-cell data.
RESULTS: TP53-mutated AML exhibited a differentiation bias toward granulocyte-monocyte and late myeloid progenitors rather than arrest at the stem cell stage, with enhanced anti-apoptotic and inflammatory programs and a transcriptionally and functionally supported ferroptosis resistance phenotype as a novel hallmark linked to poor prognosis. Functionally, CD8⁺ T cells were predominantly exhausted with an enrichment of dysfunctional subsets and a concomitant reduction of NK cells. B cells showed impaired activation with skewed plasma cell composition, and myeloid cells acquired immunosuppressive features. In the stromal compartment, mesenchymal cells lost hematopoietic and immune-supportive functions and shifted toward osteogenic programs, further reinforcing leukemic survival. We also established an integrated ecosystem score that, together with TP53 mutation burden and mono- versus multi-hit status, captured prognostic heterogeneity and enabled clinical stratification.
CONCLUSIONS: This study provides the first single-cell landscape of de novo TP53-mutated AML, highlighting its reprogrammed leukemic hierarchy and disrupted immune-stromal ecosystem, and offering mechanistic insights and potential therapeutic targets for this high-risk subtype.