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

Muhammad Furqan,Delong Liu,Nikhil Mukhi,Byung Lee

doi:10.1186/2050-7771-1-5

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.

Highlights

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway is one of the critical intracellular signaling cascades in transduction of extracellular signals to the nucleus to control gene expression
Conclusion and future directions Currently the benefits of therapy with JAK inhibitors in Myeloproliferative Neoplasms (MPN) are palliative in nature
This is suggested by inability of ruxolitinib to influence the natural history of the diseases and by the fact that the responses are unrelated to JAK mutation status

Summary

Introduction

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway is one of the critical intracellular signaling cascades in transduction of extracellular signals to the nucleus to control gene expression. A common mutation (V617F) in the JH2 pseudo-kinase domain of JAK2 was shown in 80% of the patients [21] This results in constitutive activation of STAT5 and a malignant phenotype [22]. A different mutation in JAK2 gene in a patient with Down syndrome associated precursor B-cell lymphoblastic leukemia was reported by Malinge et al, This mutation was in-frame deletion of five-amino acid residues from position 682 to 686, named as IREED mutation, in the pseudokinase domain of JAK2. This IREED mutant remains constitutively active and induces cytokine independence in Ba/F3 cells [43]. It was noticed that patients who achieved complete remission were those with post-MPN AML [65]

III: Recruiting

Results

Conclusion and future directions

Findings

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