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

•  Introduction ‐  BCR‐ABL1‐  ABL1 ‐  BCR‐ABL1‐  Anti‐BCR‐ABL1 targeted therapy in CML ‐  Imatinib resistance and second‐generation anti‐BCR‐ABL1 kinase inhibitors ‐  Other ABL1 mutations•  JAK2 and MPL mutations ‐  Janus kinases ‐  JAK2 fusion mutations‐  JAK2V617F‐  JAK2 exon 12 mutations‐  JAK2 mutations associated with trisomy 21 associated acute lymphoblastic leukaemia‐  MPL mutations ‐  Clinical and prognostic correlates of JAK2 and MPL mutations‐  Anti‐ JAK2 small molecule therapy•  KIT mutations ‐  KIT‐  Mutant KIT‐  Systemic mastocytosis ‐  Targeted therapy in systemic mastocytosis•  PDGFR mutations ‐  PDGFRA mutations ‐  PDGFRB mutations•  FGFR1 mutationsAbstract 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 ( JAK2 V617F and other JAK2 mutations), essential thrombocythemia ( JAK2 V617F and MPL5 15 mutations), primary myelofibrosis ( JAK2 V617F and MPL515 mutations), systemic mastocytosis ( KIT D816V 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.