New targets for Ph+ leukaemia therapy

The outcome for adults with Philadelphia chromosome (Ph+) leukaemias (chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL)) has been dramatically improved with the use of tyrosine kinase inhibitors (TKIs), but progression and/or relapse are still present in the majority of patients. We reviewed recent findings obtained from analysis of BCR-ABL point mutations, gene expression profiling (GEP) analysis single nucleotide polymorphism (SNP) arrays and characterised by the identification of multiple novel genetic alterations targeting key cellular pathways, including lymphoid differentiation, cell cycle, tumour suppression, apoptosis and drug responsiveness. By GEP analysis, several down/up-expressed genes have been identified. Furthermore, by SNP array analysis, deletions of genes such as IKAROS, PAX5 and CDKN2A-CDKN2B were frequently identified. New therapeutic approaches with novel TKIs are now available. Dasatinib, nilotinib and bosutinib are now in clinical development. Some emerging aurora kinase inhibitors, such as VX-680, PHA-739358, MK-0457 and AS703569, and Smo1 and Hedgehog (Hh) inhibitors promise clinical efficacy against the Bcr-Ab T315I mutant form and leukaemia stem cells, respectively. In this review, we highlight the most promising drugs for the treatment of adult BCR–ABL-positive leukaemias.