Mutation of the Lyn tyrosine kinase delays the progression of Friend virus induced erythroleukemia without affecting susceptibility.
During the initial phase of Friend virus (FV) induced erythroleukemia, the interaction between the viral envelope glycoprotein gp55, the Erythropoietin receptor (EpoR) and the naturally occurring truncated version of the Mst1r receptor tyrosine kinase, called Sf-Stk, drives the polyclonal expansion of infected progenitors in an erythropoietin independent manner. Sf-Stk provides signals that cooperate with EpoR signals to effect expansion of erythroid progenitors. The latter phase of disease is characterized by a clonal expansion of transformed leukemic cells causing an acute erythroleukemia in mice. Signaling by Sf-Stk and EpoR mediated by gp55 renders erythroid progenitors Epo independent through the activation of the EpoR downstream pathways such as PI3K, MAPK and JAK/STAT. Previous work has shown that Src family kinases also play an important role in erythropoiesis. In particular, mutation of Src and Lyn can affect erythropoiesis. In this report we analyze the role of the Lyn tyrosine kinase in the pathogenesis of Friend virus. We demonstrate that during FV infection of primary erythroblasts, Lyn is not required for expansion of viral targets. Lyn deficient bone marrow and spleen cells are able to form Epo independent FV colonies in vitro. In vivo infection of Lyn deficient animals also results in a massive splenomegaly characteristic of the virus. However, we observe differences in the pathogenesis of Friend erythroleukemia in Lyn-/- mice. Lyn-/- mice infected with the polycythemia inducing strain of FV, FVP, do not develop polycythemia suggesting that Lyn-/- infected erythroblasts have a defect in terminal differentiation. Furthermore, the expansion of transformed cells in the spleen is reduced in Lyn-/- mice. Our data show that Lyn signals are not required for susceptibility to Friend erythroleukemia, but Lyn plays a role in later events, the terminal differentiation of infected cells and the expansion of transformed cells.
Subramanian
Aparna
A
Graduate Program in Biochemistry, Microbiology and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
Hegde
Shailaja
S
Correll
Pamela H
PH
Paulson
Robert F
RF
D000818:Animals; D001853:Bone Marrow / Q000201:enzymology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000821:virology; D005622:Friend murine leukemia virus; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology / Q000235:genetics* / Q000821:virology; D007942:Leukemia, Experimental / Q000201:enzymology / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D012192:Retroviridae Infections / Q000201:enzymology / Q000235:genetics*; D013154:Spleen / Q000201:enzymology / Q000821:virology; D014412:Tumor Virus Infections / Q000201:enzymology / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics*
D017467:Receptors, Erythropoietin; D014759:Viral Envelope Proteins; D010770:Phosphotransferases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases