Single-cell mutation analysis of clonal evolution in myeloid malignancies.

Area of Science:

• Hematology
• Cancer Biology
• Genomics

Background:

• Myeloid malignancies, like acute myeloid leukaemia (AML), originate from hematopoietic stem and progenitor cells acquiring somatic mutations.
• Bulk sequencing provides insights but cannot resolve clonal architecture or mutation order.
• Understanding clonal evolution is crucial for elucidating AML pathogenesis.

Purpose of the Study:

• To delineate the clonal framework of myeloid malignancies using single-cell mutational profiling.
• To identify mutation patterns and their impact on clonal expansion and dominance in AML.
• To integrate mutational analysis with protein expression for a comprehensive view of genotype and immunophenotype.

Main Methods:

• Single-cell mutational profiling of 146 samples from 123 patients.
• Analysis of variant allele frequencies to infer mutation timing and clonal relationships.
• Mapping of clonal trajectories and identification of synergistic mutation combinations.
• Integration of protein expression data with somatic genotype and clonal architecture.

Main Results:

• AML is characterized by a few dominant clones, frequently co-mutated in epigenetic regulators.
• Mutations in signaling genes often arise independently in distinct subclones, increasing clonal diversity.
• Identified specific mutation combinations that drive clonal expansion and dominance.
• Mapped the relationship between somatic genotype, clonal architecture, and immunophenotype.

Conclusions:

• Single-cell profiling provides a high-resolution view of myeloid malignancy clonal architecture.
• Epigenetic regulator mutations contribute to dominant clone formation, while signaling mutations promote diversity.
• Understanding clonal dynamics and genotype-phenotype correlations is key to deciphering myeloid transformation and disease progression.