title: Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics.
abstract: The acute myeloid leukaemia (AML) genome contains more than 20 driver recurrent mutations. Here, we review the potential for therapeutic targeting of the most common mutations associated with normal cytogenetics AML, focusing on those affecting the FLT3, NPM1 and epigenetic modifier genes (DNMT3A, IDH1/2, TET2). As compared to early compounds, second generation FLT3 inhibitors are more specific and have better pharmacokinetics. They also show higher anti-leukaemic activity, leading to about 50% of composite complete remissions in refractory/relapsed FLT3-internal tandem duplication-mutated AML. However, rapid relapses invariably occur due to various mechanisms of resistance to FLT3 inhibitors. This issue and the best way for using FLT3 inhibitors in combination with other therapeutic modalities are discussed. Potential approaches for therapeutic targeting of NPM1-mutated AML include: (i) reverting the aberrant nuclear export of NPM1 mutant using exportin-1 inhibitors; (ii) disruption of the nucleolus with drugs blocking the oligomerization of wild-type nucleophosmin or inducing nucleolar stress; and (iii) immunotherapeutic targeting of highly expressed CD33 and IL3RA (CD123) antigens. Finally, we discuss the role of demethylating agents (decitabine and azacitidine) and IDH1/2 inhibitors in the treatment of AML patients carrying mutations of genes (DNMT3A, IDH1/2 and TET2) involved in the epigenetic regulation of transcription.
authors.affiliation: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.affiliation: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.affiliation: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Brunetti
authors.affiliation: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Martelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D016503:Drug Delivery Systems / Q000379:methods*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C571163:CD33 protein, human; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: FLT3; NPM1; acute myeloid leukaemia; epigenetic gene mutations; normal cytogenetics