A complex genetic rearrangement in a t(10;14)(q24;q11) associated with T‐cell acute lymphoblastic leukemia

Park, James K.; Beau, Michelle M. Le; Rowley, Janet D.; Dı́az, Manuel O.; Shows, Thomas B.

doi:10.1002/gcc.2870040105

Cited by 10 publications

(8 citation statements)

References 20 publications

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“…Losses in 10q and 17p were also found in the recent study of Mao et al (2002). Aberrations of the chromosome 10q region have, in addition to CTCL (Berger and Bernheim, 1987;Schlegelberger et al, 1994;Thangavelu et al, 1997), been reported for other hematological malignancies, including acute T cell leukemias (Park et al, 1992), B cell lymphomas (Siebert et al, 1998), and other non-Hodgkin lymphomas (Speaks et al, 1992). This region encodes tumor suppressor genes such as PTEN (10q23.3), MXI1 (10q25-26), and DMBT1 (10q25-26).…”

Section: Discussionmentioning

confidence: 64%

Genomic Aberrations and Survival in Cutaneous T Cell Lymphomas

Fischer

Gellrich

Muche

et al. 2004

Journal of Investigative Dermatology

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Information on chromosomal aberrations in cutaneous T cell lymphomas (CTCL), is scarce. In this study, comparative genomic hybridization (CGH) was used to analyze chromosomal imbalances (CI) in 32 patients with CTCL. CI were detected in 21 patients (66%). Euchromatic loss (dim) was localized most frequently (>16%) at the chromosomal regions 17p (28%), 13q (25%), 10q (16%), and 6q (19%), and gain of chromatin (enh) at 7 (25%), 8q (25%), and 17q (16%). The pattern dim6q-enh7-enh8-dim13 was the most frequent combination of CI. The number of aberrations per tumor sample varied between 0 and 19 and correlated with clinical tumor stages: from none in stage Ia to 8.75+/-1.8 (mean+/-SEM) in stage IVa. CI occurred more frequently in aggressive subtypes (9.33+/-2.16) than in indolent (2.88+/-0.8) subtypes. A high number of CI (>/=5) was associated with shorter survival. Gain of chromatin in 8q and loss of 6q and 13q correlated with a significantly shorter survival, whereas the most frequently observed aberrations (loss in 17p and gain in 7) did not influence the prognosis. In summary, CGH analysis revealed a characteristic pattern of recurring chromosomal gains and losses in CTCL. The association of the imbalances with the clinical course of the disease suggests that genes encoded at these loci may influence tumor development and progression.

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Section: Discussionmentioning

confidence: 64%

Genomic Aberrations and Survival in Cutaneous T Cell Lymphomas

Fischer

Gellrich

Muche

et al. 2004

Journal of Investigative Dermatology

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“…The t(10;14)(q24;q11) translocation occurs in about 10% of T-cell acute lymphoblastic leukemias. This involves a reciprocal translocation between chromosomes 10 and 14, wherein breakage on chromosome 10 occurs at the HOX11 (TCL3) gene, which encodes a transcription factor (3)(4)(5)(6). Breaks at HOX11 occur at the 5= end of the gene, due to an unknown mechanism, resulting in its juxtaposition to the T-cell receptor (TCR) locus.…”

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confidence: 99%

“…Earlier investigators had proposed a V(D)J recombinationmediated mechanism for HOX11 breakage, due to the presence of cryptic RSS near the patient breakpoints (3)(4)(5)(6). However, the cryptic sequence at the breakpoint region was shown not to be recognized by the recombination-activating gene (RAG) complex (11).…”

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confidence: 99%

G-Quadruplex Structures Formed at the HOX11 Breakpoint Region Contribute to Its Fragility during t(10;14) Translocation in T-Cell Leukemia

Nambiar

Srivastava

Gopalakrishnan

et al. 2013

Molecular and Cellular Biology

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The t(10;14) translocation involving the HOX11 gene is found in several T-cell leukemia patients. Previous efforts to determine the causes of HOX11 fragility were not successful. The role of non-B DNA structures is increasingly becoming an important cause of genomic instability. In the present study, bioinformatics analysis revealed two G-quadruplex-forming motifs at the HOX11 breakpoint cluster. Gel shift assays showed formation of both intra-and intermolecular G-quadruplexes, the latter being more predominant. The structure formation was dependent on four stretches of guanines, as revealed by mutagenesis. Circular dichroism analysis identified parallel conformations for both quadruplexes. The non-B DNA structure could block polymerization during replication on a plasmid, resulting in consistent K ؉ -dependent pause sites, which were abolished upon mutation of G-motifs, thereby demonstrating the role of the stretches of guanines even on double-stranded DNA. Extrachromosomal assays showed that the G-quadruplex motifs could block transcription, leading to reduced expression of green fluorescent protein (GFP) within cells. More importantly, sodium bisulfite modification assay showed the single-stranded character at regions I and II of HOX11 in the genome. Thus, our findings suggest the occurrence of G-quadruplex structures at the HOX11 breakpoint region, which could explain its fragility during the t(10;14) translocation.

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“…11 Cytogenetic analyses have shown that 4% of T-ALL cases contain a t(10;14)(q24q11) translocation, where the HOX11 gene is juxtaposed to the D␦2, D␦3 or J␦1 gene segments of the TCR␦ at locus 14q11. 5,[12][13][14][15][16] In addition, a variant translocation t(7;10)(q35;q24) is associated with 1% of T-ALL, such that the HOX11 gene is juxtaposed to the TCR␤ gene at locus 7q35. 16,17 Sequence analysis of 15 out of 19 reported t(10;14)(q24;q11) translocations demonstrated that the breakpoints on the 10q24 locus were clustered within a 1 kb region directly upstream of the HOX11 gene.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, studies of some t(10;14)(q24;q11) and t(7;10)(q35;q24) breakpoints have shown that heptamer and/or nonamer-like sequences which normally signal V(D)J recombination were present in the DNA flanking the 10q24 breakpoints. 1,5,[13][14][15]17,18 The net result of errors in the normal rearrangement process was the expression of a 2.3 kb transcript, when the HOX11 gene was juxtaposed to the TCR locus.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of a complex chromosomal translocation breakpoint t(10;14) including the HOX11 oncogene locus

Salvati

Thomas

et al. 1999

Leukemia

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Based on cytogenetic studies, non-random chromosomal translocations which involve the HOX11 gene at locus 10q24 and the TCR genes at loci 7q35 or 14q11 have been reported to occur in 5% of T-ALL. HOX11, a member of the homeobox family of genes, has been shown to play a role in T-ALL. The activation of the HOX11 gene by translocations to the TCR locus results in the inappropriate expression of a 2.3 kb transcript. In this paper we describe a t(10;14)(q24;q11) breakpoint from a T-ALL patient specimen. The breakpoint appears to be mediated by errors in the TCR/V(D)J recombination system, but is more complex than commonly described reciprocal translocations between the HOX11 and TCR genes, since it involves an inversion event of the TCR␦ genes. In addition, the breakpoint was characterised to a previously unsequenced area of the 10q24 locus, 3.4 kb upstream of the HOX11 gene. This breakpoint is more centromeric than the breakpoint cluster region previously shown to be involved in the majority of reported t(10;14)(q24;q11) translocations. Hence, our investigations of the translocation breakpoint in this patient identify another breakpoint region in the 10q24 locus and may define a novel recombination 'hot spot'. Surprisingly, our studies provide a mechanism for a previously unexplained complex translocation described by another group which involves the same region of the HOX11 promoter.

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A complex genetic rearrangement in a t(10;14)(q24;q11) associated with T‐cell acute lymphoblastic leukemia

Cited by 10 publications

References 20 publications

Genomic Aberrations and Survival in Cutaneous T Cell Lymphomas

Genomic Aberrations and Survival in Cutaneous T Cell Lymphomas

G-Quadruplex Structures Formed at the HOX11 Breakpoint Region Contribute to Its Fragility during t(10;14) Translocation in T-Cell Leukemia

Molecular characterization of a complex chromosomal translocation breakpoint t(10;14) including the HOX11 oncogene locus

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