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

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.

PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways

“…We then determined if our proteomics data could associate protein patterns to CNVs and SNVs validated by targeted NGS. Cyclin-dependent-kinase inhibitor 2A (CDKN2A) is a well-known tumor suppressor protein that is inactivated in pediatric leukemia 6,33 . Deletion in CDKN2A on chromosomal region 9 of p21 was detected at a rate of 62% in our sequenced B-and T-ALL sample cohort (12 samples) ( Table 3).…”

“…The Oncomine Childhood Cancer Research Assay (OCCRA) comprises 2,031 unique DNA-based amplicons to detect SNVs, and CNVs, and 1701 RNA-based amplicons to detect unique fusion or structural variants. The average read depth for the OCCRA panel was 8x10 5 -1x10 6 .…”

“…Although highly adequate for studying clinical drug assessments and blast-stromal interactions 4 , patient derived xenograft (PDX) models using immunodeficient mice do not enable investigation of leukemia immune cell interactions. Xenografts from B-cell ALL, T-ALL, and acute myeloid leukemia (AML) maintain patient-specific leukemogenic profile pertaining to the transcriptome, MRD marker expression, immunophenotype, and chromosomal aberrations [6][7][8][9][10] . DNA methylation profiling likewise revealed strong similarities in the epigenome of matched primary and xenograft blasts 11 .…”

Origins of STIL‐TAL1 fusion genes in children who later developed paediatric T‐cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots

“…Approximately 11‐27 % of children with T‐ALL present with the genetic aberration SCL/TAL1 interrupting locus ( STIL )‐T‐cell acute leukaemia ( TAL1 ) at diagnosis . STIL‐TAL1 fusion is exclusively found in T‐ALLs and based on single cell phylogenomics, is considered to be an early or initiating event in T‐ALL …”

“…10,11 STIL-TAL1 fusion is exclusively found in T-ALLs and based on single cell phylogenomics, is considered to be an early or initiating event in T-ALL. 12 Several deletions resulting in STIL-TAL1 gene fusion have been described, yet two of them, type I and type II, appear to be most common and represent 95% of total STIL-TAL1 cases and occur in 10-19% and 1-3% of paediatric patients with T-ALL, respectively. 11,13,14 Both type I and II deletions use the same cryptic heptamer recombination signal sequence at the 5 ′ break in the STIL gene but can use either one of two 3 ′ recombination signal sequences (only 1.7 kb apart) found in the 5 ′ region of TAL1.…”