Abstract
The JAK-STAT signaling pathway plays a central role in signal transduction in hematopoietic cells, as well as in cells of the immune system. The occurrence in most patients affected by myeloproliferative neoplasms (MPNs) of driver mutations resulting in the constitutive activation of JAK2-dependent signaling identified the deregulated JAK-STAT signal transduction pathway as the major pathogenic mechanism of MPNs. It also prompted the development of targeted drugs for MPNs. Ruxolitinib is a potent and selective oral inhibitor of both JAK2 and JAK1 protein kinases. Its use in patients with myelofibrosis is associated with a substantial reduction in spleen volume, attenuation of symptoms and decreased mortality. With growing clinical experience, concerns about infectious complications, and increased risk of B-cell lymphoma, presumably caused by the effects of JAK1/2 inhibition on immune response and immunosurveillance, have been raised. Evidence shows that ruxolitinib exerts potent anti-inflammatory and immunosuppressive effects. Cellular targets of ruxolitinib include various components of both the innate and adaptive immune system, such as natural killer cells, dendritic cells, T helper, and regulatory T cells. On the other hand, immunomodulatory properties have proven beneficial in some instances, as highlighted by the successful use of ruxolitinib in corticosteroid-resistant graft vs. host disease. The objective of this article is to provide an overview of published evidence addressing the key question of the mechanisms underlying ruxolitinib-induced immunosuppression.
Highlights
The majority of patients affected by classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), harbor mutations of the genes encoding for Janus kinase 2 (JAK2), thrombopoietin receptor gene (MPL), or calreticulin (CALR) [1, 2]
The substantial clinical benefits and efficacy associated with the use of JAK1/2 inhibitor therapy need to be balanced against the multiple effects on components of both innate and adaptive immunity, including natural killer cells (NKs), dendritic cells (DCs), and T cells (Th and T regulatory cells (Treg))
Ruxolitinib impairs several cytokines, modulates DCs function and T cell response and reduces NKs levels in MPNs patients, which may lead to increased risk of opportunistic infection and reactivation of latent infections
Summary
The majority of patients affected by classic Philadelphia chromosome-negative (or BCR-ABL1negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), harbor mutations of the genes encoding for Janus kinase 2 (JAK2), thrombopoietin receptor gene (MPL), or calreticulin (CALR) [1, 2]. Among patients with PV, JAK2 mutations are predominant (>95%) [4]. These so-called “driver mutations” which are mutually exclusive, result in constitutively activated JAK2 signaling and upregulation of JAK-signal transducer and activator of transcription (STAT) target genes [2, 4]. The JAK-STAT signaling pathway plays a central role in normal hematopoiesis by mediating signals from a variety of cytokines and hematopoietic growth factors, in hematopoietic stem cells [1]. It is crucial for cytokine activation and signaling in the immune system [5, 6]. Patients with MPNs, and MF, exhibit both uncontrolled myeloproliferation and abnormally elevated levels of circulating proinflammatory cytokines causing diseaserelated systemic symptoms [7]
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