Functions of BET Proteins in Normal Erythroid Gene Expression and Childhood Hematologic Cancers
Recent studies at the Center for Childhood Cancer Research and elsewhere demonstrated that small molecule inhibitors of bromodomain and extraterminal motif proteins (BETs) reduce cancer cell proliferation and enhance survival in preclinical models of solid and hematological cancers. BET inhibitors have also exhibited therapeutic potential in preclinical models of acute myeloid leukemia (AML).
While much emphasis has been placed on the role of BETs in tumor cell development, little is known about their actual role in normal cellular function and gene expression during the maturation of blood cells.
GATA1 is a master regulator of the development of specific types of blood cells from their precursor cells, termed hematopoietic progenitors or precursors. The protein plays a role in blood cell development by regulating a large ensemble of genes.
Previous studies conducted at the Center for Childhood Cancer Research revealed that GATA1, an acetylated transcription factor, interacts with several different BET proteins in a model system of hematopoietic maturation. Additional studies found that depletion of certain BET proteins blunted GATA1 driven gene activation and interfered with normal hematopoiesis.
These findings suggest that GATA1-BET interactions play an important role in normal hematopoietic gene expression. The system described here to study BET proteins is ideally suited to define the role of individual BET proteins in blood cell formation, and provides functional assays for the development of more selective inhibitors. In the long term, such selective inhibitors are expected to improve therapeutic outcomes for childhood hematologic cancers and related blood disorders.