Defining regulators of hematopoietic stem cells – novel paradigms for stem cell expansion and therapeutic targeting of leukemic cells

The molecular principles regulating hematopoietic stem cells (HSCs) remain incompletely defined.

Through development of innovative approaches to study regulation of human HSCs we aim to characterize modifiers of self-renewal and differentiation and to define novel therapeutic approaches for treatment of leukemia, either by enhancing stem cell transplantation or by selectively targeting leukemic cells.

To this end, my laboratory has developed paradigms for genome-wide functional screens in human HSCs using RNA interference libraries, and identified several new regulators of HSC function, relevant for both HSC expansion and leukemia development.

Within this research program we will extend and further develop our genetic screening paradigms using CRISPR/Cas9 to identify other modifiers of HSC renewal and differentiation.

We will further employ a nanotechnology-based delivery approach to deliver potent RNAi molecules for expansion of human HSCs under clinically relevant conditions.

Finally we will exploit the concept of synthetic lethality between members of the cohesin complex, previously identified in our screens, as a strategy to selectively eradicate leukemic cells.

The aim is that our work will advance clinical trials for expansion of transplantable HSCs to treat patients with leukemia.

Moreover we hope that these studies will define new therapeutic strategies to selectively target leukemic cells that can be further exploited clinically.