The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia

Caroline L Furness; Marcela B Mansur; Victoria J Weston; Luca Ermini; Frederik W van Delft; Sarah Jenkinson; Rosemary Gale; Christine J Harrison; Maria S Pombo-de-Oliveira; Marta Sanchez-Martin; Adolfo A Ferrando; Pamela Kearns; Ian Titley; Anthony M Ford; Nicola E Potter; Mel Greaves

doi:10.1038/s41375-018-0046-8

The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia

Leukemia. 2018 Sep;32(9):1984-1993. doi: 10.1038/s41375-018-0046-8. Epub 2018 Mar 20.

Authors

Caroline L Furness¹, Marcela B Mansur^{1

2}, Victoria J Weston³, Luca Ermini¹, Frederik W van Delft⁴, Sarah Jenkinson⁵, Rosemary Gale⁵, Christine J Harrison⁴, Maria S Pombo-de-Oliveira², Marta Sanchez-Martin⁶, Adolfo A Ferrando⁶, Pamela Kearns³, Ian Titley¹, Anthony M Ford¹, Nicola E Potter¹, Mel Greaves⁷

Affiliations

¹ Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
² Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
³ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴ Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
⁵ Department of Haematology, University College London Cancer Institute, University College London, London, UK.
⁶ Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
⁷ Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Intracellular Signaling Peptides and Proteins
Oncogene Proteins, Fusion
STIL protein, human
T-Cell Acute Lymphocytic Leukemia Protein 1
TAL1 protein, human
PTEN Phosphohydrolase
PTEN protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding