Subtle changes in clonal dynamics: Challenges in quantifying the slow expansion of small hematopoietic stem cell...

Area of Science:

• Hematology
• Computational Biology
• Genetics

Background:

• Clonal dynamics in hematopoietic stem cells (HSCs) are key to understanding blood regeneration and diseases.
• Mutations driving clonal expansion often arise early and grow slowly over decades, posing detection challenges.

Purpose of the Study:

• To investigate the limitations of quantifying small, slowly expanding clones in HSCs over short timeframes.
• To model the impact of stochasticity, measurement uncertainty, and proliferation rates on clonal dynamics.

Main Methods:

• Development of a stochastic mathematical model for clonal competition at the HSC level.
• Analysis of clonal dynamics under varying proliferation rates and observation intervals.

Main Results:

• Intrinsic stochastic fluctuations dominate early clonal competition, especially for low-abundance clones (around 1%).
• Short-term analyses may misrepresent clones as stable or shrinking due to these fluctuations.
• Increased proliferation accelerates pre-malignant clone expansion, acting as a time-lapse mechanism.

Conclusions:

• Accurate inference of clonal growth is complicated by measurement uncertainty and limited sampling.
• Short-term monitoring is insufficient for identifying and tracking slowly expanding clones.
• Extended follow-up and improved measurement precision are essential for clinical and therapeutic assessment of clonal dynamics.