Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells

• CBX7 is essential for leukemic cell survival

• Small-molecule inhibitors of CBX7 epigenetically reprogram leukemic cells and induce differentiation

Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The Polycomb group protein Chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. As leukemic cells are highly self-renewing, we tested whether pharmacological targeting CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7-inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A (H2Aub) and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.