Submitted February 23, 2009
Accepted June 14, 2009
Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling
Andrew D. Wood, Edwin Chen, Ian J. Donaldson, Shilpa Hattangadi, Karly A. Burke, Mark A. Dawson, Diego Miranda-Saavedra, Harvey F. Lodish, Anthony R. Green, and Berthold Gottgens*
Department of Hematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
Whitehead Institute for Biomedical Research, Cambridge, MA, United States
* Corresponding author; email: bg200{at}cam.ac.uk.
The discovery of JAK2V617F as an acquired mutation in the majority of patients with myeloproliferative disorders (MPDs) and the key role of the JAK2-STAT5 signalling cascade in normal hematopoiesis has focussed attention on the downstream transcriptional targets of STAT5. Despite evidence of its vital role in normal erythropoiesis and its ability to recapitulate many of the features of myeloid malignancies, including the MPDs, few functionally validated targets of STAT5 have been described. Here we used a combination of comparative genomics and chromatin immunoprecipitation assays to identify ID1 as a novel target of the JAK2-STAT5 signalling axis in erythroid cells. STAT5 binds and transactivates a downstream enhancer of ID1 and ID1 expression levels correlate with the JAK2V617F mutation in both retrovirally transfected fetal liver cells and polycythemia vera (PV) patients. Knockdown and overexpression studies in a well-characterised erythroid differentiation assay from primary murine fetal liver cells demonstrated a survival-promoting action of ID1. This hitherto unrecognised function implicates ID1 in the expansion of erythroblasts during terminal differentiation and suggests that ID1 plays an important role in the pathogenesis of PV. Furthermore, our findings contribute to an increasing body of evidence implicating ID proteins in a wider range of cellular functions than initially appreciated.
