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. 2013 Jan 16;1(1):5.
doi: 10.1186/2050-7771-1-5.

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Muhammad Furqan  1 , Nikhil Mukhi, Byung Lee, Delong Liu
Affiliations

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Muhammad Furqan et al. Biomark Res. .

Abstract

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.

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Figures

Figure 1
Figure 1
Signaling cascade of JAK-STAT pathway. Binding of the ligand to cytokine receptor induces receptor dimerization and activation of receptor associated JAK kinase, which in turn phosphorylates STAT proteins. After forming a homodimer, STAT proteins translocate to the nucleus to control gene expression. Negative regulation of the JAK-STAT pathway is provided by phospho-tyrosine phosphatases (PTP), member for SOCS family proteins and PIAS proteins (shown in red).
See this image and copyright information in PMC

References

    1. Ferrajoli A, Faderl S, Ravandi F, Estrov Z. The JAK-STAT pathway: a therapeutic target in hematological malignancies. Curr Cancer Drug Targets. 2006;6(8):671–679. doi: 10.2174/156800906779010227. - DOI - PubMed
    1. Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN. Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity. 1999;11(2):225–230. doi: 10.1016/S1074-7613(00)80097-7. - DOI - PubMed
    1. Friedrich K, Kammer W, Erhardt I, Brandlein S, Sebald W, Moriggl R. Activation of STAT5 by IL-4 relies on Janus kinase function but not on receptor tyrosine phosphorylation, and can contribute to both cell proliferation and gene regulation. Int Immunol. 1999;11(8):1283–1294. doi: 10.1093/intimm/11.8.1283. - DOI - PubMed
    1. Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD. et al.Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity. 1999;10(2):249–259. doi: 10.1016/S1074-7613(00)80025-4. - DOI - PubMed
    1. Bradley HL, Hawley TS, Bunting KD. Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells. Blood. 2002;100(12):3983–3989. doi: 10.1182/blood-2002-05-1602. - DOI - PubMed