Insights into molecular pathways for targeted therapeutics in acute leukaemia

Abstract

Despite the development of modern chemotherapeutic regimens, acute leukaemia remains incurable in the majority of adult patients and potential cure is associated with considerable side effects. Clinical and experimental research of the last two decades has demonstrated that acute leukaemia is the consequence of multiple collaborative molecular aberrations affecting protein kinases and transcriptional regulators induced by genetic alterations and/or epigenetic mechanisms. New technologies have been developed to detect aberrations of the entire (epi)genome of a leukaemic blast that will result in a long list of potential therapeutic targets needing to be functionally validated in cellular and animal leukaemia models. Using these methods, several "druggable” protein kinases have been identified. These kinases exert their oncogenic potential not only through expansion of the leukaemic clone, but also by regulating critical interactions of leukaemic stem cells with the microenvironment. Due to the molecular complexity of acute leukaemia, new functional genome-wide screens have been established and may help to identify targets that when blocked result in synthetic lethality of the leukaemic blasts harbouring distinct (epi)genomic lesions. A close interaction between the academic and the pharmaceutical biomedical research will be essential to translate these exciting new molecular findings into improved therapies for acute leukaemia.

Keywords

• acute leukemia
• fusion genes
• mutations
• pathways
• targeted
• therapy