Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling

N.S. Slavova-Azmanova; N. Kucera; J. Satiaputra; L. Stone; A. Magno; M.J. Maxwell; C. Quilici; W. Erber; S.P. Klinken; M.L. Hibbs; E. Ingley

doi:10.1182/blood-2012-10-463158

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Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling

Journal article

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Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling

N.S. Slavova-Azmanova, N. Kucera, J. Satiaputra, L. Stone, A. Magno, M.J. Maxwell, C. Quilici, W. Erber, S.P. Klinken, M.L. Hibbs, …

Blood, Vol.122(2), pp.262-271

2013

DOI: https://doi.org/10.1182/blood-2012-10-463158

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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 (Lynup/up) on erythropoiesis and Epo receptor signaling. Adult Lynup/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+ Lynup/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.

Details

Title: Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling
Authors/Creators: N.S. Slavova-Azmanova (Author/Creator) - The University of Western Australia
N. Kucera (Author/Creator) - The University of Western Australia
J. Satiaputra (Author/Creator) - The University of Western Australia
L. Stone (Author/Creator) - The University of Western Australia
A. Magno (Author/Creator) - The University of Western Australia
M.J. Maxwell (Author/Creator) - Monash University
C. Quilici (Author/Creator) - Monash University
W. Erber (Author/Creator) - The University of Western Australia
S.P. Klinken (Author/Creator) - The University of Western Australia
M.L. Hibbs (Author/Creator) - Monash University
E. Ingley (Author/Creator) - The University of Western Australia
Publication Details: Blood, Vol.122(2), pp.262-271
Publisher: American Society of Hematology
Identifiers: 991005544299107891
Copyright: © 2013 by The American Society of Hematology.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.184 Physiology & Metals; 1.184.1030 Erythropoietin Therapy
Web Of Science research areas: Hematology
ESI research areas: Clinical Medicine