Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1

• Published in: Blood 2004-12, Vol.104 (13), p.3901-3910
• Main Authors: Harder, Kenneth W., Quilici, Cathy, Naik, Edwina, Inglese, Melissa, Kountouri, Nicole, Turner, Amanda, Zlatic, Kristina, Tarlinton, David M., Hibbs, Margaret L.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - genetics; Biological and medical sciences; Colony-Forming Units Assay; Combined treatment; Erythropoiesis - genetics; Erythropoiesis - physiology; Hematopoiesis - genetics; Hematopoiesis - physiology; Inositol Polyphosphate 5-Phosphatases; Intracellular Signaling Peptides and Proteins; Medical sciences; Mice; Mice, Knockout; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - deficiency; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - physiology; Spleen - cytology; Spleen - physiology; src Homology Domains; src-Family Kinases - deficiency; src-Family Kinases - genetics; src-Family Kinases - physiology; Treatment. General aspects; Tumors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-12-4396

The Lyn tyrosine kinase plays essential inhibitory signaling roles within hematopoietic cells by recruiting inhibitory phosphatases such as SH2-domain containing phosphatase-1 (SHP-1), SHP-2, and SH2-domain containing 5′-inositol phosphatase (SHIP-1) to the plasma membrane in response to specific stimuli. Lyn-deficient mice display a collection of hematopoietic defects, including autoimmune disease as a result of autoantibody production, and perturbations in myelopoiesis that ultimately lead to splenomegaly and myeloid neoplasia. In this study, we demonstrate that loss of Lyn results in a stem/progenitor cell-intrinsic defect leading to an age-dependent increase in myeloid, erythroid, and primitive hematopoietic progenitor numbers that is independent of autoimmune disease. Despite possessing increased numbers of erythroid progenitors, and a more robust expansion of these cells following phenylhydrazine challenge, Lyn-deficient mice are more severely affected by the chemotherapeutic drug 5-fluorouracil, revealing a greater proportion of cycling progenitors. We also show that mice lacking SHIP-1 have defects in the erythroid and myeloid compartments similar to those in mice lacking Lyn or SHP-1, suggesting an intimate relationship between Lyn, SHP-1, and SHIP-1 in regulating hematopoiesis. (Blood. 2004;104:3901-3910)