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Cytogenetic classification of T lineage acute lymphoblastic leukaemia: multiple partners of BCL11B and other novel rearrangements

Cytogenetic classification of T lineage acute lymphoblastic leukaemia: multiple partners of BCL11B and other novel rearrangements
Cytogenetic classification of T lineage acute lymphoblastic leukaemia: multiple partners of BCL11B and other novel rearrangements
Increasing numbers of genetic changes are being described in T lineage acute lymphoblastic leukaemia (T ALL), which may be used to classify patients into subgroups, defining multi-step oncogenic pathways. We have integrated the significant abnormalities into a comprehensive genetic classification of T ALL, using appropriate probes for fluorescence in situ hybridization (FISH). Break-apart probes were designed, which detected rearrangements of the TCR loci. Metaphase FISH, confirmed by informative break-apart probes for the significant oncogenes, were used to identify partner genes, as shown in the table. This approach revealed new recurrent translocation partners, as well as determining the incidence and simultaneous occurrence of the different abnormalities. The series included 295 patients, children 0–14 years (n=206) and adults 15 years (n=89), with a diagnosis of T ALL, entered to one of the UK MRC/NCRI ALL treatment trials. The incidences of the common cryptic abnormalities, SIL-TAL1 fusion and TLX3 were more prevalent in children (20% and 17%, respectively) compared to adults (9% each). There was no difference in event free survival between the childhood patients with SIL-TAL1 fusion and TLX3 rearrangements. CALM-AF10 fusion and MLL rearrangements accounted for 4% each. A single patient was found with a BCR-ABL fusion, but the same probe identified nine (3%) with NUP214-ABL1 amplification. Deletions involving CDKN2A were present in 49% of patients, in association with all abnormalities. Among the patients with NUP214-ABL1 amplification, associated abnormalities were: CDKN2A deletions (n=9), TRA@-TLX1 (n=2), BCL11B-TLX3 (n=2), TRB@-TLX3 (n=1). Concurrent rearrangements were found between the TCR genes, as well as associations between MYC, IGH and the other oncogenes. For example, (1) complex abnormalities between (a) TRA@, TRG@, BCL11B (n=2) and (b) HOXA@ (n=1); (2) deletions of 3'TRB@ in association with (a) complex ring chromosomes (n=2) and (b) cytogenetically visible deletions (n=2). FISH detected several novel, recurrent rearrangements, in particular a t(6;14) involving BCL11B and the 6q26 region (n=5) and a t(9;14)(p24;q31.1) involving JAK2 (n=2), the partners of which are currently being defined. BCL11B was also involved with (a) LMO2 and (b) the 2q23 region; LMO2 was rearranged with an unidentified partner in a complex translocation with chromosomes 16 and 18; TLX1 was involved in a translocation with 3q; new partners of TRB@ were found at (a) 1q11, (b) on 12p (n=2), (c) on 21q. These findings demonstrate the valuable role of FISH analysis, with a panel of carefully selected probes, to classify T ALL patients into genetic subgroups, including rare variants, and provide information on the relationship between them. A metaphase FISH approach has facilitated the identification of potential new target genes. In particular, multiple partners of TRB@ and BCL11B, other than the known TLX3 and HOXA@ genes, have emerged, highlighting the importance of these genes in the pathogenesis of T ALL.
classification, time, leukemia
0006-4971
p.584A
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Barber, Kerry
a0901e6e-4b25-4d58-bffe-cbc4608d0847
Broadfield, Zoë
5348a91c-1f78-4b02-8313-cad685ff5197
Stewart, Adam
f892bf1d-c923-405d-a33b-cc2935b3fc20
Wright, Sarah
6f77f8df-a02c-4de5-8ddf-6ab3a50fb49a
Martineau, Mary
6cc6f57f-7b57-4583-81eb-17dac737e35c
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Barber, Kerry
a0901e6e-4b25-4d58-bffe-cbc4608d0847
Broadfield, Zoë
5348a91c-1f78-4b02-8313-cad685ff5197
Stewart, Adam
f892bf1d-c923-405d-a33b-cc2935b3fc20
Wright, Sarah
6f77f8df-a02c-4de5-8ddf-6ab3a50fb49a
Martineau, Mary
6cc6f57f-7b57-4583-81eb-17dac737e35c
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5

Harrison, Christine J., Barber, Kerry, Broadfield, Zoë, Stewart, Adam, Wright, Sarah, Martineau, Mary, Strefford, Jon C. and Moorman, Anthony V. (2006) Cytogenetic classification of T lineage acute lymphoblastic leukaemia: multiple partners of BCL11B and other novel rearrangements. Blood, 108 (11), p.584A.

Record type: Article

Abstract

Increasing numbers of genetic changes are being described in T lineage acute lymphoblastic leukaemia (T ALL), which may be used to classify patients into subgroups, defining multi-step oncogenic pathways. We have integrated the significant abnormalities into a comprehensive genetic classification of T ALL, using appropriate probes for fluorescence in situ hybridization (FISH). Break-apart probes were designed, which detected rearrangements of the TCR loci. Metaphase FISH, confirmed by informative break-apart probes for the significant oncogenes, were used to identify partner genes, as shown in the table. This approach revealed new recurrent translocation partners, as well as determining the incidence and simultaneous occurrence of the different abnormalities. The series included 295 patients, children 0–14 years (n=206) and adults 15 years (n=89), with a diagnosis of T ALL, entered to one of the UK MRC/NCRI ALL treatment trials. The incidences of the common cryptic abnormalities, SIL-TAL1 fusion and TLX3 were more prevalent in children (20% and 17%, respectively) compared to adults (9% each). There was no difference in event free survival between the childhood patients with SIL-TAL1 fusion and TLX3 rearrangements. CALM-AF10 fusion and MLL rearrangements accounted for 4% each. A single patient was found with a BCR-ABL fusion, but the same probe identified nine (3%) with NUP214-ABL1 amplification. Deletions involving CDKN2A were present in 49% of patients, in association with all abnormalities. Among the patients with NUP214-ABL1 amplification, associated abnormalities were: CDKN2A deletions (n=9), TRA@-TLX1 (n=2), BCL11B-TLX3 (n=2), TRB@-TLX3 (n=1). Concurrent rearrangements were found between the TCR genes, as well as associations between MYC, IGH and the other oncogenes. For example, (1) complex abnormalities between (a) TRA@, TRG@, BCL11B (n=2) and (b) HOXA@ (n=1); (2) deletions of 3'TRB@ in association with (a) complex ring chromosomes (n=2) and (b) cytogenetically visible deletions (n=2). FISH detected several novel, recurrent rearrangements, in particular a t(6;14) involving BCL11B and the 6q26 region (n=5) and a t(9;14)(p24;q31.1) involving JAK2 (n=2), the partners of which are currently being defined. BCL11B was also involved with (a) LMO2 and (b) the 2q23 region; LMO2 was rearranged with an unidentified partner in a complex translocation with chromosomes 16 and 18; TLX1 was involved in a translocation with 3q; new partners of TRB@ were found at (a) 1q11, (b) on 12p (n=2), (c) on 21q. These findings demonstrate the valuable role of FISH analysis, with a panel of carefully selected probes, to classify T ALL patients into genetic subgroups, including rare variants, and provide information on the relationship between them. A metaphase FISH approach has facilitated the identification of potential new target genes. In particular, multiple partners of TRB@ and BCL11B, other than the known TLX3 and HOXA@ genes, have emerged, highlighting the importance of these genes in the pathogenesis of T ALL.

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More information

Published date: 16 November 2006
Additional Information: ASH Annual Meeting Abstracts, Poster Board Session: 240-II. Abstract 2062.
Keywords: classification, time, leukemia

Identifiers

Local EPrints ID: 62780
URI: http://eprints.soton.ac.uk/id/eprint/62780
ISSN: 0006-4971
PURE UUID: f133ae13-08f0-4499-a5d5-9024aa7144f7
ORCID for Jon C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 10 Nov 2008
Last modified: 14 Mar 2019 01:43

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Contributors

Author: Christine J. Harrison
Author: Kerry Barber
Author: Zoë Broadfield
Author: Adam Stewart
Author: Sarah Wright
Author: Mary Martineau
Author: Anthony V. Moorman

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