The CBX proteins in hematopoiesis and leukemia
Hematopoietic stem cells (HSCs) are responsible for maintaining hematopoiesis. These cells are able to self-renew, but can also differentiate to all mature hematopoietic cells. Disturbance of this balance can lead to depletion or excessive production of cells, clinically translated to cytopenia or hyperproliferative conditions (e.g. leukemia). The process of self-renewal and differentiation is tightly regulated at many different levels. Among them, epigenetic factors have been shown to play a pivotal role in the regulation of HSC fate and are often deregulated in leukemia. In this thesis we focus on epigenetic modifications and mutations in leukemia and the epigenetic inhibitors that are currently in development for the treatment of different hematological malignancies. The experimental work goes deeper into the function of the protein Chromobox (CBX7), a member of the Polycomb repressive complex 1 (PRC1), an important epigenetic regulator complex. We show that among the different Chromobox proteins that can be part of this complex, only CBX7 possesses the ability to control HSC self-renewal and differentiation. We uncoverd novel crosstalk between CBX7 and other epigenetic proteins. Our analyses revealed CBX7 represses genes involved in differentiation and cell cycle control. Inhibition of CBX7 indeed reduced cell growth and led to differentiation of primitive hematopoetic cells. Our data suggest a CBX7 mediated anti-leukemic effect of these inhibitors. Together our data support that CBX7 might be a potential target for the treatment of leukemia.