title: Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling.
abstract: Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.
authors.affiliation: Cell Signalling Group, Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, WA, Australia.
authors.forename: Neli S
authors.initials: NS
authors.lastname: Slavova-Azmanova
authors.forename: Nicole
authors.initials: N
authors.lastname: Kucera
authors.forename: Jiulia
authors.initials: J
authors.lastname: Satiaputra
authors.forename: Leah
authors.initials: L
authors.lastname: Stone
authors.forename: Aaron
authors.initials: A
authors.lastname: Magno
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.forename: Cathy
authors.initials: C
authors.lastname: Quilici
authors.forename: Wendy
authors.initials: W
authors.lastname: Erber
authors.forename: S Peter
authors.initials: SP
authors.lastname: Klinken
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.forename: Evan
authors.initials: E
authors.lastname: Ingley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000743:Anemia, Hemolytic / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D053614:Janus Kinase 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt