Molecular drug targets in myeloproliferative neoplasms: Mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1

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Abstract

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g. ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above-listed mutant molecules in the context of their value as drug targets.

Original languageEnglish (US)
Pages (from-to)215-237
Number of pages23
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number2
DOIs
StatePublished - Feb 2009

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Platelet-Derived Growth Factor beta Receptor
Mutation
Gene Fusion
Pharmaceutical Preparations
Neoplasms
Systemic Mastocytosis
Molecular Targeted Therapy
Mastocytosis
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Oncogene Proteins
Eosinophilia
Genetic Association Studies
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma
Leukemia
Stem Cells
Bone Marrow
Phenotype

Keywords

  • Eosinophilia
  • Mastocytosis
  • Myelofibrosis
  • Polycythemia
  • Thrombocythemia
  • V617F

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

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title = "Molecular drug targets in myeloproliferative neoplasms: Mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1",
abstract = "Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g. ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above-listed mutant molecules in the context of their value as drug targets.",
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