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

Abstract

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. IntroductionThe production and lineage commitment of hematopoietic cells is governed by the actions of a multitude of cytokines, hormones, and growth factors that bind to cell surface receptors activating signal transduction cascades that ultimately regulate the expression of genes that control cell fate and effector function. 1 Signal propagation in these cells is actively counterbalanced by several families of inhibitory gene products including protein tyrosine phosphatases, 2 phosphatidyl-inositol phosphatases, 3 the suppressors of cytokine signaling (SOCS) proteins, 4 and receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). 5 The central role played by tyrosine phosphorylation is exemplified by mutations in particular genes that lead to deregulation of hematopoiesis. For example, mutational activation of either the Abl 6,7 or Janus tyrosine kinases [8][9][10] leads to leukemogenesis. Loss of appropriate negative regulation of signaling may also have catastrophic consequences. For example, loss-of-function mutations within the inhibitory phosphatase Src homology 2 (SH2)-containing phosphatase-1 (SHP-1) [11][12][13] in motheaten and motheaten viable mice (Me v ), or disruption of the murine SH2-domain containing 5Ј-inositol phosphatase (SHIP-1) 14,15 gene, lead to severe perturbations in hematopoiesis with myeloid cell consolidation of the lungs of deficient mice leading to premature death. [14][15][16] Thus, the appropriate balance of positive and negative elements of signal transduction is essential for maintaining normal hematopoietic cell self-renewal, differentiation, and immune cell function.Although clearly involved in initiating tyrosine-phosphorylation cascades following hematopoietic cell stimulation, 17 Lyn has emerged as a critical enzyme responsible for establishing signaling thresholds in B cells, 18-21 myelomonocytic cells, 22,23 and mast cells. [24][25][26][27][28] Indeed, loss of Lyn kinase leads to defects in activation of inhibitory phosphatases that likely underlies the hypersensitivity of deficient cells to immunoreceptor and cytokine stimulation. 20,22,29,30 In the case of B cells and mast cells, Lyn deficiency is associated with impaired activation of ...

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

“…In macrophages, loss of Lyn results in hypersensitivity to GM-CSF and M-CSF [19,34]. Previous studies have also shown that deficiency of Lyn in aged mice results in extramedullary hematopoiesis, as well as macrophage tumors in some cases [19,38]. Our studies reveal a positive role for Lyn in regulating long-term engraftment of stem cells.…”

Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells

“…Importantly, the absence of Lyn, or prolonged activation of Lyn, have deleterious consequences for the hemopoietic compartment in vivo (26,27,55). The data presented here add to the understanding of the intricate mechanisms involved in the control of Src family kinases.…”

“…Lyn remains an active kinase in erythrocytes, and is capable of phosphorylating the structural protein Band 3 (25). The effects of Lyn on erythroid cells are not restricted to in vitro systems, as Lyn Ϫ/Ϫ mice display extramedullary stress erythropoiesis and eventually become anemic (26,27).…”

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

“…41 In fact, LYN knockout mice are anemic. 42 Although there is no clear clinical link between Src inhibition by dasatinib and myelosuppression, nilotinib, which does not inhibit the Src family of kinases, has a more favorable myelosuppression profile. Further, a review of clinical trial data reveals that rates of grade 3/4 hematologic AEs for dasatinib treatment were higher than those seen with nilotinib in both CML-CP and CML-advanced phase (AP) patients.…”