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17-03-2015 | Acute lymphoblastic leukemia | Article

Genomics in acute lymphoblastic leukaemia: insights and treatment implications

Kathryn G. Roberts, Charles G. Mullighan


Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer and an important cause of morbidity from haematological malignancies in adults. In the past several years, we have witnessed major advances in the understanding of the genetic basis of ALL. Genome-wide profiling studies, including microarray analysis and genome sequencing, have helped identify multiple key cellular pathways that are frequently mutated in ALL such as lymphoid development, tumour suppression, cytokine receptors, kinase and Ras signalling, and chromatin remodeling. These studies have characterized new subtypes of ALL, notably Philadelphia chromosome-like ALL, which is a high-risk subtype characterized by a diverse range of alterations that activate cytokine receptors or tyrosine kinases amenable to inhibition with approved tyrosine kinase inhibitors. Genomic profiling has also enabled the identification of inherited genetic variants of ALL that influence the risk of leukaemia development, and characterization of the relationship between genetic variants, clonal heterogeneity and the risk of relapse. Many of these findings are of direct clinical relevance and ongoing studies implementing clinical sequencing in leukaemia diagnosis and management have great potential to improve the outcome of patients with high-risk ALL.

Nat Rev Clin Oncol 2015; 12: 344–357. doi:10.1038/nrclinonc.2015.38

Subject terms: Acute lymphocytic leukaemia • Cancer genomics • Paediatric cancer

Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer.1 Current treatment regimens result in 5-year event-free survival rates that exceed 85% in children (aged 1–21); however, disease relapse is associated with a poor outcome,2, 3 and ALL remains the leading cause of cancer-related death in children and young adults (aged 21–39).1 Although ALL is less common in adults, treatment outcomes are significantly inferior to those in children.4 The reasons underlying this age-related decline in outcome are not completely understood, but include a reduced prevalence of genetic alterations associated with a favourable outcome, such as high hyperdiploidy, presence of the ETV6–RUNX1 gene fusion and a higher incidence of genetic alterations associated with poor outcome, such as the BCR–ABL1 fusion in adults compared to children.4 Nevertheless, when compared to childhood ALL, detailed information on the genetic basis of ALL in adults is lacking. Importantly, few therapeutic strategies are available that specifically target genes or pathways known to be mutated in ALL. Development of such targeted approaches is urgently needed as currently used multiagent chemotherapy is associated with substantial short-term and long-term dose-limiting toxicities. Here, we review the current understanding of cytogenetic and molecular classification of ALL, with an emphasis on the latest insights into new entities of ALL with implications for improved clinical practice.

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