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Infer­ences of clonal dynam­ics in human hematopoiesis

Lena Nitsch – Hector RCD Awardee Leif Ludwig

The forma­tion of cells in our blood is sustained through­out our lifetime by hematopoi­etic stem cells. An under­stand­ing of the output and activ­ity of individ­ual stem cells, however, is only emerg­ing. In my project, I will inves­ti­gate clonal recon­sti­tu­tion dynam­ics and evalu­ate hematopoi­etic regen­er­a­tion utiliz­ing somatic mutations in the mitochon­dr­ial genome as natural barcodes in match­ing bone marrow and periph­eral blood samples from patients under­go­ing allogenic stem cell transplantation.

Somatic mutations accumu­late in cells through­out our lifetime and can thereby repre­sent an accurate molec­u­lar clock. Notably, this makes them ideal for under­stand­ing devel­op­men­tal and regen­er­a­tive processes of human physi­ol­ogy directly in vivo.

The hematopoi­etic system is an essen­tial organ system with long-term stable contri­bu­tion to all lineages of blood cells. The forma­tion of these individ­ual cellu­lar parts of the blood, a process referred to as hematopoiesis, is sustained by hematopoi­etic stem and progen­i­tor cells (HSPCs) which reside mainly in the bone marrow. An under­stand­ing of their lifetime dynam­ics and direct output of individ­ual stem cells in humans is, however, only emerging.

An elegant way to assess the activ­ity and output of one individ­ual stem cell and its clonal behav­ior in humans in vivo is clonal tracing by using somatic varia­tion within the mitochon­dr­ial genome. The mitochon­dr­ial genome is small enough for cost-efficient sequenc­ing but large enough to accumu­late substan­tial genetic diver­sity. Given its higher mutation rate compared to the nuclear genome, we can utilize the result­ing varia­tion as natural barcodes. Specif­i­cally, by lever­ag­ing mitochon­dr­ial DNA mutations that arise in single cell stem cells and follow­ing these mutations in longi­tu­di­nally sampled, match­ing blood and bone marrow samples after allogenic stem cell trans­plan­ta­tion, we envision to inves­ti­gate clonal recon­sti­tu­tion dynam­ics of stem cells to evalu­ate hematopoi­etic regen­er­a­tion and stem cell behav­ior in vivo, monitor resid­ual disease, and charac­ter­ize proper­ties of malig­nant cells in case of relapse.

Inferences of clonal dynamics in human hematopoiesis

Lena Nitsch

Max-Delbrück-Centrum für Moleku­lare Medizin

Super­vised by

Hector RCD Awardee Dr. Dr.

Leif S. Ludwig

Biology & Medicine

Disziplinen Dr. Dr. Leif LudwigHector RCD Awardee since 2020