The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.
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ICR Authors
Authors
Furness, CL
Mansur, MB
Weston, VJ
Ermini, L
van Delft, FW
Jenkinson, S
Gale, R
Harrison, CJ
Pombo-de-Oliveira, MS
Sanchez-Martin, M
Ferrando, AA
Kearns, P
Titley, I
Ford, AM
Potter, NE
Greaves, M
Mansur, MB
Weston, VJ
Ermini, L
van Delft, FW
Jenkinson, S
Gale, R
Harrison, CJ
Pombo-de-Oliveira, MS
Sanchez-Martin, M
Ferrando, AA
Kearns, P
Titley, I
Ford, AM
Potter, NE
Greaves, M
Document Type
Journal Article
Date
2018-09-01
Date Accepted
2017-12-18
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.
Citation
Leukemia, 2018, 32 (9), pp. 1984 - 1993
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Biology of Childhood Leukaemia