Role of Stem Cells in Normal and Malignant Hematopoiesis

Although insults to the blood-forming system highlight the need for more rapid blood replenishment from hematopoietic stem cells (HSCs), existing models of hematopoiesis implicate only one, mandatory, differentiation pathway for each blood lineage.

We have evidence for non-hierarchical relationships between mouse HSCs replenishing all blood lineages and exclusively platelets through distinct pathways.

We will investigate the role of these 2 pathways and the replenished platelets at different stages of ontogeny and in response to different challenges, using single HSC transplantations, genetic fate mapping and single cell RNA sequencing, with the goal of providing a platform for combatting transplantation-and drug-induced thrombocytopenia.

It remains unclear to what degree the extensive steady-state turn-over of blood cells can progress in absence of HSCs, a question with important implications also for the cancer stem cell hypothesis, implying that efficient therapeutic targeting of the malignant stem cells might be sufficient to eliminate the entire malignancy.

No studies have addressed this following efficient and selective elimination of stem cells in vivo.

Herein we aim to  engineer T cell receptors (TCRs) that efficiently and specifically target antigens selectively and highly expressed on normal and malignant HSCs to establish if elimination of the rare malignant stem cells is not only required, but potentially sufficient for a cure.