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  • Review Article
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The genetics and mechanisms of T cell acute lymphoblastic leukaemia

Key Points

  • T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological tumour resulting from the malignant transformation of T cell progenitors.

  • T-ALL is biologically and genetically heterogeneous with gene expression signatures that identify different clinico-biological groups associated with T cell arrest at different stages of thymocyte development.

  • Oncogenic NOTCH signalling resulting from activating mutations in NOTCH1 is a major driver of T-ALL transformation.

  • Aberrant expression of transcription factor oncogenes as a result of chromosomal translocations and other chromosomal rearrangements is common in T-ALL.

  • Recurrent mutations and deletions in T-ALL frequently involve cell cycle regulators, but also transcription factors, tumour suppressors, epigenetic factors and negative regulators of NOTCH1, Janus kinase (JAK)–signal transducer and activator of transcription (STAT), PI3K and MAPK signalling.

  • Relapsed T-ALL is associated with a poor prognosis, and relapse-associated activating mutations in the cytosolic 5′-nucleotidase II gene, NT5C2, induce resistance to 6-mercaptopurine chemotherapy.

Abstract

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic.

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Figure 1: Intrathymic T cell development.
Figure 2: Oncogenic programmes and gene expression signatures define distinct molecular groups of T-ALL.
Figure 3: The NOTCH1 signalling pathway.
Figure 4: Oncogenic forms of NOTCH1 in T-ALL.

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Acknowledgements

The authors thank P. Van Vlieberghe for his insightful comments and suggestions. This work was supported by funding by the US National Institutes of Health (R01 CA172398, R01 CA177319, R01 CA155743, R01 CA129382 and R01 CA120196). The authors apologize to those whose work could not be mentioned owing to space limitations.

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Glossary

Neutropenia

Abnormally low neutrophil count in the blood.

Thrombocytopenia

Abnormally low platelet count in the blood.

Mediastinal thymic masses

Enlargement of the thymus, often indicative of lymphoma.

Thymocyte

Haematopoietic progenitor cell present in the thymus.

B precursor ALL

A haematological tumour derived from B cell progenitors arrested at early stages of B cell development. It is characterized by diffuse infiltration of the bone marrow with leukaemic cells expressing immature B cell markers.

Early T-lineage progenitor cells

The most immature cells in the thymus with the developmental potential to complete T-lineage development.

Leukaemia initiating cell

Leukaemia cell with intrinsic self-renewal capacity and the ability to generate all leukaemia populations in tumour transplantation assays.

Long non-coding RNAs

(lncRNAs). Non-protein-coding transcripts longer than 200 nucleotides, which are now recognized to have roles in the regulation of gene expression.

X-linked severe combined immunodeficiency syndrome

An immunodeficiency disorder characterized by defective T cell and natural killer cell generation as a result of loss-of-function mutations in the interleukin-2 receptor-γ (IL2RG) gene, which encodes a common component of the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors.

Pre-TCR

A signalling factor composed of a T cell receptor-β (TCRβ) coupled with the invariable pre-TCRα protein, which triggers the proliferation, survival and differentiation of thymocytes during their development following TCRB rearrangement.

Platelet disorder, familial, with associated myeloid malignancy

(FPDMM). A leukaemia predisposition syndrome characterized by a moderate decrease in platelet numbers and an increased risk of acute myeloid leukaemia and T cell acute lymphoblastic leukaemia caused by loss-of-function mutations in the runt related transcription factor 1 (RUNX1) gene.

Börjeson–Forssman–Lehmann syndrome

(BFLS). A rare X-linked genetic syndrome characterized by intellectual deficit, truncal obesity, characteristic facial features, hypogonadism, tapered fingers and short toes. It is caused by mutations in the PHD finger protein 6 (PHF6) gene.

Eukaryotic translation initiation factor 4A

(eIF4A). A protein translation initiation complex with RNA helicase activity required for the binding of mRNA to 40S ribosomal subunits.

Thiopurine

A purine antimetabolite broadly used in the treatment of acute lymphoblastic leukaemia, in which the oxygen atom at carbon 6 of hypoxanthine (6-mercaptopurine) or guanine (6-thioguanine) has been replaced by sulfur.

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Belver, L., Ferrando, A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer 16, 494–507 (2016). https://doi.org/10.1038/nrc.2016.63

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