Genotype-immunophenotype relationships in NPM1-mutated AML clonal evolution uncovered by single-cell multiomic...

Area of Science:

• Hematology
• Cancer Biology
• Genomics

Background:

• Acute myeloid leukemia (AML) is a multi-clonal hematopoietic malignancy.
• Bulk sequencing methods limit understanding of AML clonal architecture and evolution during therapy.
• NPM1-mutated AML presents a unique model to study clonal dynamics.

Purpose of the Study:

• To investigate the clonal evolution and genotype-immunophenotype relationships in NPM1-mutated AML.
• To analyze how clonal complexity changes from diagnosis to relapse and during treatment.
• To understand the impact of signaling mutations on AML progression and patient survival.

Main Methods:

• Simultaneous single-cell molecular profiling and immunophenotyping.
• Analysis of 43 samples from 32 NPM1-mutated AML patients at various disease stages.
• Longitudinal sampling during front-line AML therapy.

Main Results:

• Diagnosis and relapse AML samples share similar clonal architecture.
• Signaling mutations significantly increase clonal complexity at relapse, correlating with overall survival.
• Unique genotype-immunophenotype relationships were identified, suggesting mutation-driven lineage trajectories.
• Dynamic clonal and immunophenotypic changes were observed during therapy.

Conclusions:

• Clonal architecture in NPM1-mutated AML is influenced by signaling mutations, particularly at relapse.
• Genotype-immunophenotype correlations are established early and persist throughout disease progression.
• Single-cell profiling provides critical insights into AML clonal dynamics and therapeutic response.