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 (JAK2 V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2 V617F 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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Histological hallmarks that distinguish myelodysplastic syndrome (MDS) from myelo-proliferative neoplasm (MPN) and MDS/MPN. CML, chronic myelogenous leukaemia; PV, polycythemia vera; ET, essential thrombocythemia; MF, primary myelofibrosis; CEL, chronic eosinophilic leukaemia; HES, hypereosinophilic syndrome; SM, systemic mastocytosis; CNL, chronic neutrophilic leukaemia; MPN-U, MPN, unclassifiable; CMML, chronic myelomonocytic leukaemia; JMML, juvenile myelomono-cytic leukaemia; MDS/MPN-U, MDS/MPN, unclassifiable.