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Leukemia. 2018 Sep;32(9):1984-1993. doi: 10.1038/s41375-018-0046-8. Epub 2018 Mar 20.

The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.

Author information

1
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
2
Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
3
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
4
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
5
Department of Haematology, University College London Cancer Institute, University College London, London, UK.
6
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
7
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. mel.greaves@icr.ac.uk.

Abstract

Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

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