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Genomics in acute lymphoblastic leukaemia: insights and treatment implications

Nature Reviews Clinical Oncology volume 12, pages 344–357 (2015)Cite this article

Subjects

Key Points

  • Acute lymphoblastic leukaemia (ALL) is comprised of multiple subtypes with constellations of chromosomal rearrangements, deletions and gains of DNA, and sequence mutations that target common cellular pathways

  • The prevalence of ALL subtypes varies significantly with age

  • ALL is commonly a polyclonal disease and specific genetic alterations influence the risk of drug resistance, treatment failure and disease relapse

  • Philadelphia (Ph)-chromosome-like ALL is common in children with high-risk ALL, and adults with ALL and is characterized by genetic alterations activating kinase signalling pathways, which are sensitive to tyrosine-kinase inhibitors

  • Common inherited genetic variants in lymphoid transcription factors and tumour-suppressor genes influence the risk of developing ALL, and are associated with ALL subtype and ethnicity

  • Rare mutations have been identified that drive the development of familial ALL

Abstract

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.

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Figure 1: Prevalence of ALL subtypes across age groups.
Figure 2: Frequency of genetic subtypes in patients with Ph-like ALL.49

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Acknowledgements

The authors thank their colleagues at St Jude Children's Research Hospital, the Children's Oncology Group and the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments (TARGET) consortium. Several of the studies described were supported by the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, the National Cancer Institute of the US National Institutes of Health, Alex's Lemonade Stand Foundation, the American Association for Cancer Research, the American Society of Haematology, the Henry Schueler 41&9 Foundation, the Leukemia and Lymphoma Society, the National Health and Medical Research Council (Australia), the Pew Charitable Trusts, Stand Up To Cancer and the St Baldrick's Foundation.

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  1. Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 342, Memphis, 38105, TN, USA

    Kathryn G. Roberts & Charles G. Mullighan

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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and edited the manuscript before submission.

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Correspondence to Charles G. Mullighan.

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Roberts, K., Mullighan, C. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol 12, 344–357 (2015). https://doi.org/10.1038/nrclinonc.2015.38

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