Clonal dynamics after allogeneic haematopoietic cell transplantation.

Area of Science:

• Hematology
• Immunology
• Genetics

Background:

• Allogeneic hematopoietic cell transplantation (HCT) involves replacing a patient's blood stem cells with donor cells.
• Understanding long-term stem cell engraftment dynamics post-HCT is crucial for assessing transplant success and patient health.
• Donor age significantly impacts the number of engrafted stem cells contributing to hematopoiesis years after transplantation.

Purpose of the Study:

• To quantify the dynamics of long-term stem cell engraftment after HLA-matched sibling HCT.
• To compare clonal diversity and expansion patterns between donor and recipient hematopoietic stem cells.
• To identify selection mechanisms driving stem cell behavior post-transplantation.

Main Methods:

• Genome sequencing of 2,824 single-cell-derived hematopoietic colonies from ten donor-recipient pairs.
• Analysis of samples collected 9-31 years after HCT.
• Phylogenetic analysis to infer stem cell expansion and selection modes.

Main Results:

• Younger donors had 5,000-30,000 engrafted stem cells; older donors had tenfold fewer.
• Engrafted cells contributed multilineage hematopoiesis, but clones showed lineage biases.
• Recipients exhibited reduced clonal diversity (10-15 years accelerated aging) due to 25-fold greater stem cell clone expansion.
• Two selection modes, 'pruning' and 'growth,' were identified, not a transplant bottleneck.

Conclusions:

• HCT exaggerates selective pressures on stem cells, accelerating the loss of clonal diversity compared to unperturbed hematopoiesis.
• Stem cell selection occurs both pre-transplant (pruning) and post-engraftment (growth), particularly in clones with driver mutations.
• Donor age is a critical factor influencing the long-term engraftment potential and diversity of hematopoietic stem cells.