The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL

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Despite advances in the management of acute lymphoblastic leukaemia (ALL), current regimens fail to significantly transform outcomes for patients with high-risk subtypes. Advances in genomic analyses have identified novel lesions including mutations in genes that encode chromatin modifiers and those that influence cytokine and kinase signalling, rendering many of these alterations potentially targetable by tyrosine kinase and epigenetic inhibitors currently in clinical use. Although specific genomic lesions, gene expression patterns, and immunophenotypic profiles have been associated with specific clinical outcomes in some cancers, the application of precision medicine approaches based on these data has been slow. This approach is complicated by the reality that patients often harbour multiple mutations, and in many cases, the precise functional significance and interaction of these mutations in driving leukaemia and drug responsiveness/resistance remains unknown. Given that signalling pathways driving leukaemic pathogenesis could plausibly result from the co-existence of specific lesions and the resultant perturbation of protein interactions, the use of combined therapeutics that target multiple aberrant pathways, according to an individual’s mutational profile, might improve outcomes and lower a patient’s risk of relapse. Here we outline the genomic alterations that occur in T cell ALL (T-ALL) and early T cell precursor (ETP)-ALL and review studies highlighting the possible effects of co-occurring lesions on leukaemogenesis and drug response.

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P.T.S. acquired the literature and data, designed and wrote the manuscript. L.N.E. contributed to the concept and design of the manuscript. All authors critically read and revised the manuscript.

Correspondence to Deborah L. White.

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This study was undertaken with the financial support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government through the Department of Health.

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Tavakoli Shirazi, P., Eadie, L.N., Heatley, S.L. et al. The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL. Br J Cancer (2019) doi:10.1038/s41416-019-0647-7

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