New mechanisms of resistance in Philadelphia chromosome acute lymphoblastic leukemia.

The outcome for adults and children with Philadelphia chromosome acute lymphoblastic leukemia (ALL) has been improved dramatically with the use of tyrosine kinase inhibitors but relapse is an expected event in the majority of patients. We reviewed recent findings obtained from both gene-expression profiling analysis and single nucleotide polymorphism arrays and characterized by the identification of multiple novel genetic alterations targeting key cellular pathways, including lymphoid differentiation, cell cycle, tumor suppression, apoptosis and drug responsiveness. By gene-expression profiling analysis a new subtype known as 'BCR-ABL1-like' was identified, which includes 15-20% of all precursor B-ALL cases and is associated with an unfavorable outcome. By single nucleotide polymorphism array analysis, deletions of genes such as IKAROS, PAX5 and CDKN2A-CDKN2B were frequently identified. New therapeutic approaches are now available, such as dasatinib, nilotinib and bosutinib, and we highlight those that may be applicable to the treatment of adult BCR-ABL1-positive ALL.