Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage

Kenneth W. Harder, Linda M. Parsons, Jane Armes, Natalie Evans, Nicole Kountouri, Roslyn Clark, Cathy Quilici, Dianne Grail, George S. Hodgson, Ashley R. Dunn, Margaret L. Hibbs

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132 Citations (Scopus)

Abstract

To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn -/- mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (Mφ) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.

Original languageEnglish
Pages (from-to)603-615
Number of pages13
JournalImmunity
Volume15
Issue number4
DOIs
Publication statusPublished - 1 Jan 2001

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