Clonal dynamics and mitochondrial dysfunction in hematopoiesis following chemotherapy

Chemotherapy can cause significant damage to healthy tissues, especially in the hematopoietic system.

As a result, cancer survivors may experience bone marrow damage manifested as cytopenias, which increase the risk of infections and bleeding.

Despite this, there has not been a thorough examination of these events, including the clonal dynamics of hematopoiesis after chemotherapy exposure, due to a lack of methodologies to perform lineage tracing in humans in vivo.

To address this, I will study the effects of chemotherapy on the clonal dynamics of hematopoiesis, mitochondrial dysfunction and genetic integrity in young cancer survivors.

I will analyze samples obtained before, during, and after treatment using emerging single-cell multi-omic approaches to effectively capture mitochondrial DNA (mtDNA) genetic variation for inferences of clonal dynamics and studies of mtDNA damage.

By combining mtDNA-based clonal inferences with whole-genome sequencing (WGS)-based detection of somatic nuclear DNA mutations, I will provide deep phylogenies with scalable single-cell resolved clonal measurements of perturbed hematopoiesis following chemotherapy.

Moreover, orthogonal analysis of DNA methylation and chromatin accessibility data will yield new molecular insights into chemotherapy-induced accelerated aging and mitochondrial dysfunction (a hallmark of aging).

This project sets out to gain quantitative and fundamental insights into the long-term molecular defects of chemotherapy in young cancer survivors, potentially paving the way for new interventions to improve the quality of life of this emergent population.