The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.
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Date
2018-09-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line, Tumor
Animals
Humans
Disease Models, Animal
Intracellular Signaling Peptides and Proteins
Oncogene Proteins, Fusion
In Situ Hybridization, Fluorescence
Mutation
Polymorphism, Single Nucleotide
Alleles
Adolescent
Adult
Child
Child, Preschool
Infant
PTEN Phosphohydrolase
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Genome-Wide Association Study
Young Adult
Single-Cell Analysis
Multiplex Polymerase Chain Reaction
Clonal Evolution
Heterografts
T-Cell Acute Lymphocytic Leukemia Protein 1
Research team
Biology of Childhood Leukaemia
Language
eng
Date accepted
2017-12-18
License start date
2018-09
Citation
Leukemia, 2018, 32 (9), pp. 1984 - 1993
Publisher
NATURE PUBLISHING GROUP