JAK-STAT in lymphoproliferative disorders

In the early 1990’s several groups were searching for the molecular basis of the signal transduction triggered by the engagement of plasma membrane receptors. The laboratories of Darnell, Kerr and Stark were first to identify proteins, which acted as intermediaries in interferon (IFN) signaling, known as the signal transducer and activator of transcription (STAT). At the same time, the work of Pellegrini’s, Ihle’s and Carter-Su’s groups demonstrated that non-receptor tyrosine kinases, previously described by John Krolewski and Andrew Wilks, called Janus Kinases (JAK), played a role in cytokine receptor signaling. We have since learned that multiple negative regulators, mainly tyrosine phosphatase (SHP), Protein Inhibitors Against Stats (PIAS), and Suppressor Of Cytokine Signaling (SOCS) proteins, modulate and eventually extinguish JAK-STAT signaling [1]. In invertebrates a single JAK-STAT module controls anti-viral and anti-bacterial responses, leukocytelike hemocyte generation, cell fate determination, brain development, cardiogenesis, as well as intestinal stem cells. The increase of JAK-STAT pathway components has coincided with the emergence of adaptive immunity and the expansion and diversification of cytokine receptors. As ligands bind to cognate receptors, they trigger the recruitment and activation of JAKs. Activated JAKs can then phosphorylate the receptor favoring the STAT docking and ultimately their activation via tyrosine phosphorylation. Phospho-STAT dimers accumulate in the cell nucleus, bind to enhancer elements and regulate gene expression. In parallel, JAKs may fire other downstream signaling cascades (MAP kinase and PI-3-kinase/AKT pathways), or within the nucleus by phosphorylating DNA regulatory proteins (histone H3 and methyltransferase) modulate gene expression and the epigenetic program of cells [2]. There is comprehensive evidence that abnormal JAK/STAT signals can lead to immunodeficiencies, a spectrum of cytokine mediated inflammatory diseases and cancer. Hyperactivation of STAT signaling is common in hematopoietic disorders through several different mechanisms [2-3]. JAK2 amplification, loss of SOCS1 and phosphatases, as well as somatic mutations of STAT3 and STAT6 are seen in mediastinal B-cell, grey zone, Hodgkin and Diffuse Large B-cell lymphomas. Activating mutations of JAK1-3 and STAT3-5 were also found in a subset of NK/T-cell, non-hepatosplenic gamma-delta T-cell lymphoma and T-cell prolymphocytic leukemia. Moreover, the constitutive activation of STAT is also observed in cells carrying tyrosine kinase fusions. This is epitomized in Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) fusions. In these settings, STAT3 inhibition inevitably leads to cell cycle arrest followed by apoptosis [4-5] . Searching for genomic defects responsible for the transformation and the maintenance of the neoplastic phenotype of ALKALCL, our groups have used massive genomic sequencing. These studies demonstrated the presence of recurrent activating mutations of JAK1 and/ or STAT3 and novel tyrosine kinase fusions. JAK1 and STAT3 mutants result in a hyperactivated STAT3, which sustains cell transformation, and whose pharmacological ablation produces tumor cell growth inhibition. Interestingly, we found that ~30% of systemic pSTAT3 positive ALKALCL carry both JAK1 and STAT3 mutations that work synergistically [5]. Further analyses Editorial