Single-cell analysis based dissection of clonality in myelofibrosis

Area of Science:

• Genomics
• Evolutionary Biology
• Oncology

Background:

• Cancer develops through genomic evolution, mirroring Darwinian selection.
• Clonal evolution and somatic mutations drive malignant phenotypes and tumor progression.

Purpose of the Study:

• To investigate the clonal evolution structure in myelofibrosis (MF) patients undergoing JAK inhibitor therapy.
• To analyze the acquisition of somatic mutations and copy number aberrations over time during treatment.

Main Methods:

• Whole-exome sequencing at multiple time points in 15 MF patients.
• Longitudinal follow-up (mean 3.9 years) with JAK inhibitor treatment.
• Single-cell genotyping of circulating CD34+ progenitor cells.

Main Results:

• JAK inhibition did not induce a clear evolutionary bottleneck.
• Observed complex clonal architecture, with unrelated clones emerging over time.
• Disease progression correlated with increased genetic heterogeneity and RAS/RTK pathway mutations.
• Clonal diversity led to clone-specific expansion within myeloid lineages.
• Reconstructed MF phylogeny revealed loss of heterozygosity and parallel evolution as recurrent events.

Conclusions:

• JAK inhibitor therapy in MF leads to complex clonal evolution rather than a simple bottleneck.
• Increased genetic heterogeneity and specific pathway mutations are associated with disease progression.
• Understanding clonal dynamics is crucial for managing myelofibrosis progression.