Enforced Granulocyte/Macrophage Colony-stimulating Factor Signals Do Not Support Lymphopoiesis, but Instruct Lymphoid to Myelomonocytic Lineage Conversion
Open Access
- 19 May 2003
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 197 (10), 1311-1322
- https://doi.org/10.1084/jem.20021843
Abstract
We evaluated the effects of ectopic granulocyte/macrophage colony-stimulating factor (GM-CSF) signals on hematopoietic commitment and differentiation. Lineage-restricted progenitors purified from mice with the ubiquitous transgenic human GM-CSF receptor (hGM-CSFR) were used for the analysis. In cultures with hGM-CSF alone, hGM-CSFR–expressing (hGM-CSFR+) granulocyte/monocyte progenitors (GMPs) and megakaryocyte/erythrocyte progenitors (MEPs) exclusively gave rise to granulocyte/monocyte (GM) and megakaryocyte/erythroid (MegE) colonies, respectively, providing formal proof that GM-CSF signals support the GM and MegE lineage differentiation without affecting the physiological myeloid fate. hGM-CSFR transgenic mice were crossed with mice deficient in interleukin (IL)-7, an essential cytokine for T and B cell development. Administration of hGM-CSF in these mice could not restore T or B lymphopoiesis, indicating that enforced GM-CSF signals cannot substitute for IL-7 to promote lymphopoiesis. Strikingly, >50% hGM-CSFR+ common lymphoid progenitors (CLPs) and >20% hGM-CSFR+ pro-T cells gave rise to granulocyte, monocyte, and/or myeloid dendritic cells, but not MegE lineage cells in the presence of hGM-CSF. Injection of hGM-CSF into mice transplanted with hGM-CSFR+ CLPs blocked their lymphoid differentiation, but induced development of GM cells in vivo. Thus, hGM-CSF transduces permissive signals for myeloerythroid differentiation, whereas it transmits potent instructive signals for the GM differentiation to CLPs and early T cell progenitors. These data suggest that a majority of CLPs and a fraction of pro-T cells possess plasticity for myelomonocytic differentiation that can be activated by ectopic GM-CSF signals, supporting the hypothesis that the down-regulation of GM-CSFR is a critical event in producing cells with a lymphoid-restricted lineage potential.Keywords
This publication has 74 references indexed in Scilit:
- Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in miceOncogene, 2000
- Analysis of mechanisms involved in the prevention of γ irradiation-induced apoptosis by hGM-CSFOncogene, 2000
- Bcl-2 Rescues T Lymphopoiesis, but Not B or NK Cell Development, in Common γ Chain–Deficient MiceImmunity, 1997
- Bcl-2 Can Rescue T Lymphocyte Development in Interleukin-7 Receptor–Deficient Mice but Not in Mutant rag-1−/− MiceCell, 1997
- Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem CellScience, 1996
- Simultaneous occurrence of myelomonocytic leukemia and multiple myeloma: Involvement of common leukemic progenitors and their developmental abnormality of “lineage infidelity”Journal of Cellular Physiology, 1991
- CD4 expressed on earliest T-lineage precursor cells in the adult murine thymusNature, 1991
- T cell receptor and immunoglobulin gene rearrangements in acute myeloblastic leukemia.The Journal of Experimental Medicine, 1986
- Phenotypic conversion of acute leukaemia from T‐lymphoblastic to myeloblastic induced by therapy with 2′‐deoxycoformycinBritish Journal of Haematology, 1983
- A stochastic model of self‐renewal and commitment to differentiation of the primitive hemopoietic stem cells in cultureJournal of Cellular Physiology, 1982