Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Understanding tumor protein 53 (TP53) mutations is vital for designing effective cancer therapies.
• TP53 mutations drive clonal evolution and transformation in various cancers, including acute myeloid leukemia (AML).
• Identifying genetic and non-genetic factors influencing TP53-mutant leukemogenesis is a critical research area.

Purpose of the Study:

• To investigate the genetic and non-genetic determinants of TP53-mutation-driven clonal evolution in secondary AML (sAML).
• To analyze the role of chronic inflammation in the fitness advantage of TP53-mutant hematopoietic stem/progenitor cells (HSPCs).
• To identify therapeutic strategies for TP53-mutant leukemia based on understanding its evolution.

Main Methods:

• Allelic resolution single-cell multi-omic analysis of HSPCs from patients with myeloproliferative neoplasms transforming to sAML.
• Analysis of serial patient samples and in vivo perturbations to study clonal dynamics.
• Assessment of leukemia stem cell transcriptional signatures for outcome prediction in independent AML cohorts.

Main Results:

• Dominant TP53 'multihit' HSPC clones were observed at transformation in all patients.
• A leukemia stem cell transcriptional signature predicted adverse outcomes in both TP53-mutant and wild-type (WT) AML.
• Chronic inflammation was identified as a factor suppressing TP53 WT HSPCs and enhancing the fitness of TP53-mutant cells, promoting genetic evolution.

Conclusions:

• Chronic inflammation plays a significant role in the progression of TP53-mutant leukemia by altering HSPC fitness.
• The findings provide insights into the mechanisms of clonal evolution in TP53-mutant sAML.
• This research supports the development of risk stratification, early detection, and novel treatment strategies for TP53-mutant leukemias and other cancers.