Role of JAK2 Beyond Myeloproliferative Neoplasms (MPNs): Rationale for Targeting the JAK-STAT Pathway in Other Hematological Malignancies and Solid Tumors

Abstract

Janus kinases (JAKs) are a family of receptor-associated tyrosine kinases which are crucial for the survival and proliferation of immune and hematopoietic-derived cells. There are four mammalian JAKs identified to date: JAK1, JAK2, JAK3 and TYK2 (Lopez et al., 2010). JAKs are responsible for mediating the intracellular signaling of numerous growth factors and cytokines (Murray et al., 2007 & O’Shea et al., 2002). Once activated JAKs directly phosphorylate and activate the transcription factors signal transducers and activators of transcriptions (STATs) which transduce JAK signaling by translocating to the nucleus to modulate a subset of genes that are critical for cell proliferation and survival (Aaronson et al., 2002 & Levy et al., 2002). Dysregulated JAK signaling has been implicated in the pathogenesis of several blood-borne cancers but most notably in myeloproliferative neoplasms (MPNs) (Nelson et al., 2006; Lucia et al., 2011 & Patnaik et al., 2009). MPNs are hematological malignancies defined by the excessive proliferation of one or more myeloidderived cells. MPNs are classified into two clinical categories either BCR-ABL-positive (BCR-ABL (+)) or BCR-ABL-negative (BCR-ABL (-)) based on the presence of the BCR-ABL fusion protein. The major BCR-ABL (-) MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The specific pathogenic role that JAK2 has in driving some of these MPNs is highlighted by the recent seminal discovery of the JAK2V617F mutation (Baxter et al., 2005; James et al., 2005; Kralovics et al., 2005; & Levine et al., 2005). The JAK2V617F mutation is a somatic, gain-of function point mutation which leads to constitutive activation of JAK2 and subsequent downstream activation of STATs (Baxter et al., 2005 & James et al., 2005). Current data demonstrates that JAK2 is a disease associated gene involved in the pathogenesis of BCR-ABL (-) MPNs. However, it remains unclear if JAK2 pathway mutations are the primary drivers of sustained disease progression. New data is emerging that suggests that targeting the JAK-STAT pathway may have implications beyond the treatment of MPN and can be useful for the treatment of other hematological and non-hematological cancers. This review will summarize the pathogenic role of JAKSTAT signaling in BCR-ABL (-) MPNs and introduce the potential broader implications by