The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia
| Autor: | Furness, CL, Braga Mansur, M, 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Adolescent Oncogene Proteins Fusion Intracellular Signaling Peptides and Proteins PTEN Phosphohydrolase Infant Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Polymorphism Single Nucleotide Article Clonal Evolution Disease Models Animal Young Adult Cell Line Tumor Child Preschool Mutation Animals Heterografts Humans Single-Cell Analysis Child Multiplex Polymerase Chain Reaction Alleles In Situ Hybridization Fluorescence T-Cell Acute Lymphocytic Leukemia Protein 1 Genome-Wide Association Study |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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