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Suppressor of cytokine signaling-3 is overexpressed in erythroid precursors of myelodysplastic syndrome

Leukemia volume 20, pages 1620–1621 (2006)Cite this article

Anemia represents the most common hematologic deficit affecting patients with myelodysplastic syndrome (MDS), and contributes to morbidity and mortality over time through complications related to iron overload.1 Development of new therapeutics for MDS has been challenged by the difficulty in identifying pathogenetically relevant targets that contribute to ineffective erythropoiesis. Clonogenic response to erythropoietin (EPO) is impaired in MDS despite normal cytokine receptor display and intact ligand binding capacity. EPO receptor activation of the signal transduction and activator of transcription (STAT)-5 and globin transcription factor 1 (GATA-1) is impaired in myelodysplastic erythroid progenitors supporting an intrinsic disturbance in receptor–signal transduction.2 Indeed, despite preserved proliferative response to EPO, apoptosis supercedes with differentiation, exacerbated in part by hematopoietic inhibitory cytokines within the marrow microenvironment.3

The EPO receptor is a class I cytokine receptor that lacks intrinsic kinase activity, and thereby signals through the activation of constitutively associated cytoplasmic tyrosine kinases such as the janus tyrosine kinase-2 (Jak2).4 Ligand-induced conformational change in the EPO receptor homodimer activates Jak2 phosphorylation of tyrosine residues on the receptor cytoplasmic tail, which serve as docking sites for adaptor proteins and the consequent recruitment of the STAT5a/b transcription factors to the signaling platform.5 Upon phosphorylation by Jak2, STAT5 homodimerizes and translocates to the nucleus, where it activates transcription of genes controlling the proliferation and survival of erythroid cells as well as negative regulators of the cytokine signal. Included among the latter is the suppressors of cytokine signaling (SOCS) gene family, which is comprised of eight members that share a central Src homology-2 (SH2) domain, a conserved carboxy-terminal sequence termed the SOCS box, and a variable N-terminus (reviewed by Kile and Alexander6). Transient activation of SOCS-3, also known as STAT-induced STAT inhibitor-3 (SSI-3) or cytokine-induced SH2 protein 3 (CIS3), plays a key regulatory role in EPO signal attenuation in addition to other cytokine receptors. Indeed, the SOCS-3 null phenotype is embryonically lethal at days 12–16 owing to excessive erythrocytosis, whereas transgene-forced expression of SOCS-3 blocks fetal erythropoiesis while increasing in vitro proliferation of primitive erythroid progenitors. SOCS-3 is constitutively expressed in transformed erythroleukemia cell lines where its expression has been implicated in the maturation arrest and impaired differentiation capacity. Constitutive expression of SOCS-3 has been reported in other human malignancies such as cutaneous T-cell lymphoma, and in chronic myeloid leukemia (CML) where it is believed to contribute to interferon resistance.6

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Acknowledgements

This work was supported by a University of Arizona Faculty Small Grants Program Research Award and by National Cancer Institute Grant 5 PO1 CA17094.

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Authors and Affiliations

  1. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    A F Baker, W R Tate & W B Bair III

  2. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    W Bellamy

  3. H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

    R Heaton & A F List

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Correspondence to A F Baker.

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Baker, A., Bellamy, W., Tate, W. et al. Suppressor of cytokine signaling-3 is overexpressed in erythroid precursors of myelodysplastic syndrome. Leukemia 20, 1620–1621 (2006). https://doi.org/10.1038/sj.leu.2404322

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