B-lymphopoiesis is stopped by mobilizing doses of G-CSF and is rescued by overexpression of the anti-apoptotic protein Bcl2

• Published in: Haematologica (Roma) Vol. 98; no. 3; pp. 325 - 333
• Main Authors: Winkler, Ingrid G, Bendall, Linda J, Forristal, Catherine E, Helwani, Falak, Nowlan, Bianca, Barbier, Valerie, Shen, Yi, Cisterne, Adam, Sedger, Lisa M, Levesque, Jean-Pierre
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01-03-2013
• Subjects: Animals; B-Lymphocyte Subsets - drug effects; B-Lymphocyte Subsets - metabolism; Bone Marrow - drug effects; Cyclophosphamide - pharmacology; Gene Expression; Granulocyte Colony-Stimulating Factor - administration & dosage; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds - pharmacology; Lymphopoiesis - drug effects; Lymphopoiesis - genetics; Male; Mice; Precursor Cells, B-Lymphoid - drug effects; Precursor Cells, B-Lymphoid - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Spleen - drug effects; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2012.069260

Osteoblasts are necessary to B lymphopoiesis and mobilizing doses of G-CSF or cyclophosphamide inhibit osteoblasts, whereas AMD3100/Plerixafor does not. However, the effect of these mobilizing agents on B lymphopoiesis has not been reported. Mice (wild-type, knocked-out for TNF-α and TRAIL, or over-expressing Bcl-2) were mobilized with G-CSF, cyclophosphamide, or AMD3100. Bone marrow, blood, spleen and lymph node content in B cells was measured. G-CSF stopped medullar B lymphopoiesis with concomitant loss of B-cell colony-forming units, pre-pro-B, pro-B, pre-B and mature B cells and increased B-cell apoptosis by an indirect mechanism. Overexpression of the anti-apoptotic protein Bcl2 in transgenic mice rescued B-cell colony forming units and pre-pro-B cells in the marrow, and prevented loss of all B cells in marrow, blood and spleen. Blockade of endogenous soluble TNF-α with Etanercept, or combined deletion of the TNF-α and TRAIL genes did not prevent B lymphopoiesis arrest in response to G-CSF. Unlike G-CSF, treatments with cyclophosphamide or AMD3100 did not suppress B lymphopoiesis but caused instead robust B-cell mobilization. G-CSF, cyclophosphamide and AMD3100 have distinct effects on B lymphopoiesis and B-cell mobilization with: 1) G-CSF inhibiting medullar B lymphopoiesis without mobilizing B cells in a mechanism distinct from the TNF-α-mediated loss of B lymphopoiesis observed during inflammation or viral infections; 2) CYP mobilizing B cells but blocking their maturation; and 3) AMD3100 mobilizing B cells without affecting B lymphopoiesis. These results suggest that blood mobilized with these three agents may have distinct immune properties.