Abstract
Simple SummaryJanus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is a crucial cell signaling pathway that drives the development, differentiation, and function of immune cells and has an important role in blood cell formation. Mutations targeting this pathway can lead to overproduction of these cell types, giving rise to various hematological diseases. This review summarizes pathogenic JAK/STAT activation mechanisms and links known mutations and translocations to different leukemia. In addition, the review discusses the current therapeutic approaches used to inhibit constitutive, cytokine-independent activation of the pathway and the prospects of developing more specific potent JAK inhibitors.Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.
Highlights
Introduction published maps and institutional affilCytokine signaling regulates the proliferation, differentiation, and maintenance of cells during hematopoiesis and ensures that a balance of different cell types is maintained in physiological and different stress situations
myeloproliferative neoplasms (MPNs) include primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) that can progress to acute myeloid leukemia (AML), as well as the CML, which is characterized by the BCR-ABL1 translocation, the so-called Philadelphia chromosome
Janus kinases drive hematopoiesis and immunity, and aberrant JAK activation plays a crucial role in the pathogenesis of leukemia
Summary
JAKs are non-receptor tyrosine kinases that constitutively associate with the cytoplasmic region of cytokine receptors and mediate signaling from approximately 60 cytokines and hormones [2]. Binding of a cytokine to the extracellular region of the cytokine receptor initiates signal transduction, leading to receptor rearrangement and/or dimerization, and the associated JAKs undergo conformational changes leading to trans-phosphorylation of the kinase domains and stimulation of kinase activity (reviewed in References [13,14]). JAKs serve as triggering kinases for cytokine signaling and in addition to STATs, they activate other signaling pathways including MAPK (MEK and P38) and PI3K (Ak1, RS1, and RPS6) pathways which play crucial roles in the proliferation, survival, and differentiation of hematopoietic cells [14,16]. The JH2 domain in JAK2 is responsible for S523 and Y570 phosphorylation, and as these sites are not conserved in other JAKs, this regulation appears to be specific for JAK2 and possibly in the homodimeric receptor signaling [20,21]
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