Antagonistic effect of CCAAT enhancer-binding protein-alpha and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors.
Lymphoid lineage-committed progenitors, such as common lymphoid progenitors (CLPs), maintain a latent myeloid differentiation potential, which can be initiated by stimulation through exogenously expressed cytokine receptors, including IL-2 receptors. Here we show that the transcription factor CCAAT enhancer-binding protein-alpha (C/EBPalpha) is promptly up-regulated in CLPs upon ectopic IL-2 stimulation. Enforced C/EBPalpha expression is sufficient to initiate myeloid differentiation from CLPs, as well as from proT and proB cells, even though proB cells do not give rise to myeloid cells after ectopic IL-2 stimulation. Expression of Pax5, a B lymphoid-affiliated transcription factor, is completely suppressed by enforced C/EBPalpha but not by ectopic IL-2 stimulation in proB cells. Introduction of Pax5 blocks ectopic IL-2 receptor-mediated myeloid lineage conversion in CLPs. These data suggest that C/EBPalpha is a proximal target of cytokine-induced lineage conversion in lymphoid progenitors. Furthermore, complete loss of Pax5 expression triggered by up-regulation of C/EBPalpha is a critical event for lineage conversion from lymphoid to myeloid lineage in CLPs and proB cells.
Hsu
Chia-Lin
CL
Department of Immunology, Duke University Medical Center, DUMC 3010, Research Drive, Durham, NC 27710, USA.
King-Fleischman
Angela G
AG
Lai
Anne Y
AY
Matsumoto
Yukie
Y
Weissman
Irving L
IL
Kondo
Motonari
M
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D053646:Interleukin-2 Receptor beta Subunit; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology*; D051757:PAX5 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D022763:CCAAT-Enhancer-Binding Protein-alpha; C508020:IL2RB protein, human; C508022:Il2rb protein, mouse; D053646:Interleukin-2 Receptor beta Subunit; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D015375:Receptors, Interleukin-2