Avian Models to Study the Transcriptional Control of Hematopoietic Lineage Commitment and to Identify Lineage-Specific Genes

Abstract

E26 is an avian acute leukemia virus with a profound ability to transform multipotent hematopoietic progenitor cells both in vivo and in vitro. Progenitor cells transformed by this virus can be expanded in vitro as undifferentiated clones for up to two months and can also be induced to differentiate into cells of the erythroid, eosinophilic, thrombocytic, and myelomonocytic lineages with reproducible kinetics. Aside from the proliferative stimulus provided by the E26 oncoprotein, these cells are remarkably similar to normal hematopoietic progenitors. They therefore provide an ideal assay system for determining the influence of ectopically expressed transcription factors on both maturation and commitment to several hematopoietic lineages. Results from experiments using this system suggest that subtle shifts in the balance of lineage-restricted transcription factors can result in profound changes in phenotype and challenge the notion that lineage commitment is a uni-directional process. Analysis of the regulatory elements governing the expression of these genes has provided novel mechanistic insights into the transcriptional control of hematopoiesis. In addition to their utility in deciphering the control of lineage commitment, the ability to grow large numbers of undifferentiated and more mature hematopoietic cells has facilitated the discovery of a number of novel, lineage-restricted genes. Analysis of the proteins encoded by these genes is helping to clarify the role of a number of membrane proteins in the interaction between hematopoietic cells and their microenvironments.