Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1.
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.
Harder
Kenneth W
KW
Ludwig Institute for Cancer Research, PO Box 2008, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
Quilici
Cathy
C
Naik
Edwina
E
Inglese
Melissa
M
Kountouri
Nicole
N
Turner
Amanda
A
Zlatic
Kristina
K
Tarlinton
David M
DM
Hibbs
Margaret L
ML
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D003114:Colony-Forming Units Assay; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000502:physiology; D018909:src Homology Domains; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054645:Protein Phosphatase 1; D010744:Phosphoric Monoester Hydrolases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases