ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling.
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 signaling cascade in normal hematopoiesis has focused 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 signaling 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 patients. Knockdown and overexpression studies in a well-characterized erythroid differentiation assay from primary murine fetal liver cells demonstrated a survival-promoting action of ID1. This hitherto unrecognized function implicates ID1 in the expansion of erythroblasts during terminal differentiation and suggests that ID1 plays an important role in the pathogenesis of polycythemia vera. Furthermore, our findings contribute to an increasing body of evidence implicating ID proteins in a wider range of cellular functions than initially appreciated.
Wood
Andrew D
AD
Department of Hematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Chen
Edwin
E
Donaldson
Ian J
IJ
Hattangadi
Shilpa
S
Burke
Karly A
KA
Dawson
Mark A
MA
Miranda-Saavedra
Diego
D
Lodish
Harvey F
HF
Green
Anthony R
AR
Göttgens
Berthold
B
D000818:Animals; D002469:Cell Separation; D041905:Erythroid Cells / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012190:Retroviridae / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2