title: Small-molecule inhibitors in myeloproliferative neoplasms: are we aiming for the right targets?
abstract: The ATP-binding pocket of the kinase domain of JAK2 is the major target of the present treatment of myeloproliferative neoplasms. Several inhibitors of JAK2 that are ATP competitive have been developed, but they do not discriminate between wild-type and mutant JAK2. These inhibitors have been used in myelofibrosis and, for the first time, treatment induced a reduction in spleen size and in constitutional symptoms. However, no dramatic effects on BM fibrosis, allele burden, or peripheral blast numbers were observed. These data indicate that other avenues should be explored that would either target mutant molecules (JAKs or receptors) more specifically and spare wild-type JAK2 or that would address other pathways that contribute to the malignant proliferation. Future success in treating myeloproliferative neoplasms will depend on advances of the understanding of JAK-STAT signaling and also on a better understanding of the disease pathogenesis, especially the role that mutants in spliceosome factors and epigenetic regulators play in the phenotype of the disease and the precise mechanism of fibrosis development.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium. stefan.constantinescu@bru.licr.org
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
mesh_terms: D000483:Alleles; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D044127:Epigenesis, Genetic; D005355:Fibrosis / Q000378:metabolism; D006405:Hematology / Q000379:methods*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D055728:Primary Myelofibrosis / Q000188:drug therapy; D018121:Receptors, Cytokine / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism
chemical_list: D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2