Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis.
Myelofibrosis (either primary or postpolycythemia vera/essential thrombocythemia) is a chronic and debilitating myeloproliferative neoplasm for which there is no well-accepted standard of care. Clinical manifestations of this disease (e.g., cytopenias, splenomegaly, bone marrow fibrosis) and constitutional symptoms (e.g., hypercatabolic state, fatigue, night sweats, fever) create significant treatment challenges. For example, progressive splenomegaly increases the risk for more serious clinical sequelae (e.g., portal hypertension, splenic infarction). Myelofibrosis arises from hematopoietic stem cells or early progenitor cells. However, the molecular mechanisms underlying its pathogenesis and clinical presentation are poorly understood, delaying the development of effective and targeted treatments. Recent studies have implicated mutations that directly or indirectly lead to the deregulated activation of Janus-activated kinase 2 (JAK2). Appreciation for the activation of JAK2 and the importance of increased levels of circulating proinflammatory cytokines in the pathogenesis and clinical manifestations of myelofibrosis has led to novel therapeutic agents targeting JAKs. This review will briefly discuss the origins of the JAK2 hypothesis, the clinical relevance of JAK2 mutations in myelofibrosis, and recent clinical progress in targeting JAKs as a therapeutic intervention for patients with this chronic and debilitating disease.
Verstovsek
Srdan
S
M.D. Anderson Cancer Center, Houston, TX 77030, USA. sverstov@mdanderson.org
D000818:Animals; D054697:Cytostatic Agents / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008954:Models, Biological; D050505:Mutant Proteins / Q000502:physiology; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D054697:Cytostatic Agents; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2