Single-cell profiling reveals reprogrammed hierarchy and disrupted immune-stromal ecosystem in TP53-mutated AML

Area of Science:

• Hematology
• Cancer Biology
• Genomics

Background:

• TP53-mutated acute myeloid leukemia (AML) is a high-risk subtype with poorly understood resistance and relapse mechanisms.
• Understanding the cellular and microenvironmental factors is crucial for improving outcomes in TP53-mutated AML.

Purpose of the Study:

• To delineate the cellular hierarchy, transcriptional landscape, and microenvironmental interactions in de novo TP53-mutated AML using single-cell RNA sequencing.
• To identify novel mechanisms of resistance and potential therapeutic targets in this aggressive AML subtype.

Main Methods:

• Single-cell RNA sequencing of bone marrow from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type).
• Systematic analysis of leukemic, immune, and stromal compartments.
• In vitro assays to validate findings on ferroptosis resistance, T-cell dysfunction, and stromal remodeling.

Main Results:

• TP53-mutated AML exhibits myeloid progenitor bias, enhanced anti-apoptotic/inflammatory programs, and ferroptosis resistance.
• Immune cells show exhaustion (CD8+ T cells), dysfunction (NK cells), impaired B-cell activation, and immunosuppressive myeloid cells.
• Stromal mesenchymal cells shift to osteogenic programs, losing supportive functions and promoting leukemic survival.
• An integrated ecosystem score, TP53 mutation burden, and hit status predict prognostic heterogeneity.

Conclusions:

• This study presents the first single-cell landscape of de novo TP53-mutated AML.
• It reveals a reprogrammed leukemic hierarchy and a disrupted immune-stromal ecosystem.
• Mechanistic insights and potential therapeutic targets for high-risk TP53-mutated AML are provided.