Introduction to the review series on transcription factors in hematopoiesis and hematologic disease

In this issue of Blood is a set of 6 reviews focusing on hematopoietic transcription factors. Transcription factors are DNA-binding proteins that initiate and regulate the activity of genes.¹  At present, the Encyclopedia of DNA Elements (ENCODE) project has described the genome-wide occupancy of more than 150 such proteins, a subset of which have specific roles in normal and malignant hematopoiesis.²  Previously, the topic of hematopoietic transcription factors has been covered in comprehensive reviews that provide an overview of the roles of many different factors, or in focused, in-depth reviews of a single transcription factor. We recruited 6 reviews on 4 different transcription factors to create this review series. We believe that this series of reviews provides the readers of Blood with comprehensive information, while at the same time giving an in-depth look at individual transcription factors and their roles in normal and malignant hematopoiesis.

Transcription factors are pleiotropic, often having different roles in different cells at different stages of development or differentiation. This is perhaps best exemplified by the transcription factor SCL/TAL. The review provided by Porcher and colleagues³  highlights the requirement for SCL/TAL for the specification of mesoderm and eventually hematopoietic cells during development. Once hematopoiesis has begun, SCL/TAL interacts with other transcription factors to promote differentiation in maturing myeloid cells, whereas dysregulated expression of SCL/TAL leads to T-cell acute lymphoblastic leukemia. The central role of transcription factors in normal hematopoiesis and their altered expression or activity in hematologic malignancies is a recurring theme in this review series.

One of the 3 members of the RUNX family of transcription factors, RUNX1 is required for the emergence of definitive hematopoietic stem cells during development and for normal stem cell function. The review by de Bruijn and Dzierzak⁴  traces the fundamental observations of RUNX function in normal developmental hematopoiesis and how RUNX1 performs multiple functions. The companion review by Sood and colleagues⁵  covers the role of RUNX factors in hematologic disease, which ranges from germ line mutations that cause familial platelet disorder with associated myeloid malignancies to acquired mutations that cause acute myeloid leukemia (AML) and many other disorders.

Although SCL/TAL and RUNX affect the most primitive hematopoietic cells, other transcription factors are expressed and function mainly in specific hematopoietic lineages. The review by Avellino and Delwel⁶  focuses on the myeloid transcription factor, C/EPBα. In normal hematopoiesis, C/EPBα expression promotes myeloid differentiation and is critical for neutrophil maturation. An exciting aspect of this review is the mechanistic explanation of how C/EPBα expression can be altered by mutations in the CEBPA gene as well as by other oncogenes to cause AML.

The GATA factors are a 6-member family of transcription factors with distinct roles at specific stages of development and in specific tissues. The review by Katsumura and Bresnick⁷  covers the basic biology of the GATA factors, ranging from how they interact with DNA to how GATA1 and GATA2 replace each other during hematopoietic differentiation. A highlight of this review is the focus on the interaction of GATA1 with cofactors and chromatin remodeling proteins to execute its many functions during erythropoiesis. The companion review by Crispino and Horwitz⁸  focuses on hematopoietic disorders that are associated with mutations in GATA1 and GATA2. Given that we are beginning to understand the pleiotropic and overlapping roles of the GATA factors in hematopoiesis, it should come as no surprise that acquired and inherited GATA mutations are associated with diverse clinical manifestations, including Diamond-Blackfan anemia, acute megakaryoblastic leukemia, and congenital dyserythropoietic anemia with thrombocytopenia (GATA1), as well as myelodysplastic syndromes, AML, and blast crisis transformation in chronic myeloid leukemia (GATA2). Together these reviews highlight the fast-moving field of transcription factor biology that is reshaping our understanding of normal and malignant hematology.