TY - JOUR
T1 - The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia
AU - Furness, Caroline L.
AU - Mansur, Marcela B.
AU - Weston, Victoria J.
AU - Ermini, Luca
AU - van Delft, Frederik W.
AU - Jenkinson, Sarah
AU - Gale, Rosemary
AU - Harrison, Christine J.
AU - Pombo-de-Oliveira, Maria S.
AU - Sanchez-Martin, Marta
AU - Ferrando, Adolfo A.
AU - Kearns, Pamela
AU - Titley, Ian
AU - Ford, Anthony M.
AU - Potter, Nicola E.
AU - Greaves, Mel
N1 - Funding Information:
Acknowledgements We thank Mrs Susan M Colman for assistance with FISH protocols; Dr Claire Schwab for identification of STIL-TAL1 samples and Ms Tracey Perry for assistance with in vivo experiments. We acknowledge the ECOG group for the use of the sample 21922 and the Bloodwise Childhood Leukaemia Cell Bank for provision of primary haematological malignancy samples used in this study. We thank Dr Elli Papaemmanuil for the use of the weighted matrix algorithm for assessment of RAG recombinase activity. CLF was supported by a clinical research training fellowship from Blood-wise (formerly, Leukaemia & Lymphoma Research) (grant number 11035). MBM was supported by the Partner Fellowship (European Haematology Association #2011/01); by the International Award for Research in Leukaemia (Lady Tata Memorial Trust) and by the Ministry of Health (INCA-Brazil). MSM was supported by Rally Foundation fellowship. AAF was supported by NIH (grant R35 CA210065) and Leukemia and Lymphoma Society (R0749-14). MG is supported by a Wellcome Trust award [105104/Z/14/Z] to the Centre for Evolution and Cancer.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044208474&partnerID=8YFLogxK
U2 - 10.1038/s41375-018-0046-8
DO - 10.1038/s41375-018-0046-8
M3 - Article
C2 - 29556024
AN - SCOPUS:85044208474
SN - 0887-6924
VL - 32
SP - 1984
EP - 1993
JO - Leukemia
JF - Leukemia
IS - 9
ER -