Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms

Mol Diagn Ther. 2012 Oct;16(5):269-83. doi: 10.1007/s40291-012-0006-3.

Abstract

Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alleles
  • Benzamides / therapeutic use
  • Bridged-Ring Compounds / therapeutic use
  • Carbazoles / therapeutic use
  • Chromatin / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Humans
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Mutation
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / pathology*
  • Myeloproliferative Disorders / therapy*
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • Pyrrolidines / therapeutic use
  • Receptors, Thrombopoietin / genetics
  • Receptors, Thrombopoietin / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Spliceosomes / metabolism
  • Sulfonamides / therapeutic use

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • ASXL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Benzamides
  • Bridged-Ring Compounds
  • Carbazoles
  • Chromatin
  • DNA-Binding Proteins
  • IKZF1 protein, human
  • INCB018424
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyrimidines
  • Pyrrolidines
  • Receptors, Thrombopoietin
  • Repressor Proteins
  • SH2B3 protein, human
  • Sulfonamides
  • TET2 protein, human
  • MPL protein, human
  • Ikaros Transcription Factor
  • Fedratinib
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • lestaurtinib
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Proto-Oncogene Proteins c-cbl
  • JAK2 protein, human
  • Janus Kinase 2
  • CBL protein, human