Characterizing and targeting CBX7 activity in leukemia

Leukemia, also known as blood cancer, is a disease in which the body produces too many abnormal white blood cells (leukemic cells), which outcompete healthy cells. Without treatment, leukemia patients will die due to the lack of healthy blood cells or due to metastases. Fortunately, treatment options for leukemia patients have greatly improved over recent years, and many types of leukemia can now be cured. These treatments target specific mutated proteins and thereby block the function of these malignant proteins. Unfortunately, leukemia patients who do not have mutations in these proteins cannot benefit from the recent developments and remain dependent on chemotherapy and intensive stem cell transplants.

Remarkably, mutations often affect epigenetic proteins. Epigenetics is the ‘operating system’, of a cell, and epigenetic proteins ensure whether genes are activated or not. In leukemia, this ‘operating system’ becomes dysregulated, whereby genes important for maturation are no longer activated. Therefore, leukemic cells cannot fully develop into functional blood cells. The aim of this thesis is to therapeutically restore the ‘operating system’ in leukemic cells. To achieve this goal, it was decided to target the epigenetic protein CBX7 because this protein suppresses genes necessary to inhibit growth and stimulate maturation. This thesis shows that ‘CBX7 inhibitors’ indeed reactivate genes, whereby leukemic cells stop growing, do mature, and eventually die. Finally, because CBX7 is rarely mutated, this treatment appears effective for a wide range of leukemia types and could potentially be further developed for a large group of leukemia patients.