Erg in stem cells: a function emerges

Abstract

The transcription factor Erg has presented a challenging problem for researchers for over two decades since its discovery. Strongly linked to the pathogenesis of many cancers and noteworthy in its expression pattern, in vitro transcriptional activity and genomic linkages, the Erg proto-oncogene has nevertheless resisted conventional reverse-genetic approaches for defining its normal functions in vivo. In this issue of Nature Immunology, Loughran et al. now report a considerable advance toward the clarification of this gene's importance. Using the classic forward-genetics approach of a phenotypic screen on a 'sensitized background' (discussed below), these investigators have obtained a missense mutation of Erg that is probably the first lesion to cause a distinct loss of function of this transcription factor. This mutation turns out to have profound effects on definitive hematopoiesis and especially on the hematopoietic stem cell compartment. Erg gene dosage is shown to be so critical that a strong effect on stem cell function is present even in the heterozygous state.