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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.

Original publication

DOI

10.1038/s41375-018-0046-8

Type

Journal article

Journal

Leukemia

Publication Date

09/2018

Volume

32

Pages

1984 - 1993

Keywords

Adolescent, Adult, Alleles, Animals, Cell Line, Tumor, Child, Child, Preschool, Clonal Evolution, Disease Models, Animal, Genome-Wide Association Study, Heterografts, Humans, In Situ Hybridization, Fluorescence, Infant, Intracellular Signaling Peptides and Proteins, Multiplex Polymerase Chain Reaction, Mutation, Oncogene Proteins, Fusion, PTEN Phosphohydrolase, Polymorphism, Single Nucleotide, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Single-Cell Analysis, T-Cell Acute Lymphocytic Leukemia Protein 1, Young Adult