title: Novel therapies for myelofibrosis.
abstract: Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2(V617F) mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e. mammalian target of rapamycin/AKT/phosphoinositide 3-kinase) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.
authors: a Northwestern University Feinberg School of Medicine , Chicago , IL , USA.|b Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University , Chicago , IL , USA.
authors: Brady L
authors: BL
authors: Stein
authors: c Hospital Clínic, Hematology Department, Institut d'Investigació Biomédica August Pi i Sunyer , University of Barcelona , Barcelona , Spain.
authors: Francisco
authors: F
authors: Cervantes
authors: b Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University , Chicago , IL , USA.
authors: Francis
authors: F
authors: Giles
authors: d Department of Haematology , Guy's and St. Thomas' National Health Service Foundation Trust , London , UK.
authors: Claire N
authors: CN
authors: Harrison
authors: e Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.
authors: Srdan
authors: S
authors: Verstovsek
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D053612:Janus Kinases
keywords: Molecular genetics; myeloproliferative disorders; signaling therapies