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

To investigate the role of the Lyn kinase in establishing signaling thresho lds in hematopoietic cells, a gain-of-function mutation analogous to the Sr c Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mi ce displayed no propensity toward hematological malignancy. By contrast, an alysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myel oid progenitors, and monocyte/macrophage (MO) 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 signali ng may predispose mice lacking this putative protooncogene to tumorigenesis .