Regardless, there is considerable desire for developing JAK inhibitors for the treatment of these disorders. the aberrant fusion gene was discovered, another molecular pathway, the Janus kinase (JAK)-transmission transducer and activator of transcription Cediranib (AZD2171) (STAT) pathway that regulate cell differentiation, proliferation and survival, was also described . Further elucidation and insights into potential initiating events in candidate hematological and other cancers, however, occurred only in the past decade, following the seminal discovery of the mutation in patients with myeloproliferative neoplasms (MPN) in 2005 [5-8]. The mutation confers constitutive kinase activity resulting in cytokine hypersensitivity and abnormal hematopoiesis in such patients. These observations Cediranib (AZD2171) led to efforts in developing JAK inhibitors as targeted therapies for patients with MPN. Much of what we have learned about the JAK-STAT pathway stems from the work conducted around the molecular basis of the effects of various cytokines. Preclinical research on cytokines, such as interferons (IFN), erythropoietins, and diverse growth factors (GFs) confirmed their importance for hematopoiesis, cell proliferation, survival, differentiation, and immune and inflammatory responses [9,10]. It is now well established that this JAK-STAT pathway is usually pivotal to signaling by cytokine receptors and select GFs, and centrally implicated in diverse myeloid and lymphoid malignancies as well as several solid tumors (Physique 1) . This understanding has now paved the way for new FA-H targeted treatments to be developed for diseases that appear dependent on the JAK-STAT signaling [12,13]. Open in a separate window Physique 1 Pathologic activation of autocrine JAK signaling pathways in hematologic malignancies. Schematic depiction of the multiple autocrine signaling loops recognized in B-lymphoma cells: enhanced interleukin-13 (IL-13) signaling via amplified JAK2 with downstream activation of STAT6, MYD88 mutations activating JAK-STAT3 signaling through IL-6 secretion, and activation of IL-6 and IL-10 secretion and activation of JAK-STAT1 signaling by type I interferons (IFN). Abbreviations: IFNAR, interferon alpha receptor; MAP, mitogen-activated protein; Cediranib (AZD2171) NF-B, nuclear factor B; RTK, receptor tyrosine kinase; TYK2, tyrosine kinase 2. Adapted with permission from . This review, based in part on a roundtable conversation amongst academic experts at the 54th American Society of Hematology Annual Getting together with in Atlanta, Georgia, focuses on recent improvements in the understanding of the biology of the JAK-STAT pathway in hematological malignancies, and discusses the potential therapeutic benefits of JAK inhibitors for such patients. Cytokines and the JAK-STAT Signaling Pathway The JAK family is comprised of four cytoplasmic tyrosine kinases, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), which exhibit considerable diversity in their functions: JAK1 and JAK2 using a broader role in hematopoiesis, neural development, host defense and now considered to have a causal role in a number of hematological malignancies; JAK3 and TYK2 are implicated principally in immune responses. The STAT family comprise of seven DNA-binding proteins, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT 6. Of the STAT proteins, STAT3, STAT5a and STAT5b have a broad and crucial transcription role in survival, proliferation and self-renewal; in contrast, STAT1, STAT2, STAT4 and STAT6 appear to have a more restricted role, primarily in immunoregulation [14,15]. Both JAKs and STATs mediate signaling by binding with the cytoplasmic domains of various cytokine and GF receptors. Recent efforts have confirmed the notion of the previously inactive JAKs, which are in close proximity to the cytokine/GF receptors Cediranib (AZD2171) cytoplasmic region, being activated upon binding with the cognate cytokine/GF and resulting in cross-phosphorylation.