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Rare double-hit with two translocations involving IGH both, with BCL2 and BCL3, in a monoclonal B-cell lymphoma/leukemia.

Alpatov R, Carstens B, Harding K, Jarrett C, Balakhani S, Lincoln J, Brzeskiewicz P, Guo Y, Ohene-Mobley A, LeRoux J, McDaniel V, Meltesen L, Minka D, Patel M, Manavi C, Swisshelm K - Mol Cytogenet (2015)

Bottom Line: Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3.Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

View Article: PubMed Central - PubMed

Affiliation: Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, 3055 Roslyn Street, Suite 200, Denver, CO 80238 USA.

ABSTRACT

Background: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus.

Case presentation: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.

Conclusions: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

No MeSH data available.


Related in: MedlinePlus

a Representative karyotype of the second clone. The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of a translocation between 14q and 18q (IGH;BCL2, red arrows), in addition to a 14q and 19q translocation (IGH;BCL3, white arrows). Six copies of chromosome 12 are underlined. b FISH analysis of the second clone using dual fusion IGH;BCL2 probe (green/red). Black and white image for IGH signal shows 8 loci indicating that all IGH sequences are rearranged and present on derivative chromosomes 14, 18, and 19. Black and white image for BCL2 signal shows 6 loci which represent two intact and two derivative chromosomes 18, and two derivative chromosomes 14. Merged image shows green IGH signals and red BCL2 signals which overlap in four loci, arrows (two copies of derivative chromosome 14 and two copies of derivative chromosome 18). Right panel, IGH break-apart probe (green/red) signal showing four green and four red foci indicative of the presence of four rearranged IGH loci
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Fig3: a Representative karyotype of the second clone. The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of a translocation between 14q and 18q (IGH;BCL2, red arrows), in addition to a 14q and 19q translocation (IGH;BCL3, white arrows). Six copies of chromosome 12 are underlined. b FISH analysis of the second clone using dual fusion IGH;BCL2 probe (green/red). Black and white image for IGH signal shows 8 loci indicating that all IGH sequences are rearranged and present on derivative chromosomes 14, 18, and 19. Black and white image for BCL2 signal shows 6 loci which represent two intact and two derivative chromosomes 18, and two derivative chromosomes 14. Merged image shows green IGH signals and red BCL2 signals which overlap in four loci, arrows (two copies of derivative chromosome 14 and two copies of derivative chromosome 18). Right panel, IGH break-apart probe (green/red) signal showing four green and four red foci indicative of the presence of four rearranged IGH loci

Mentions: Cytogenetic studies of bone marrow preparations from this patient revealed two related abnormal clones in eight of twenty-two metaphase spreads examined. The first clone (stemline [sl]), six cells, contained a translocation between the long (q) arm of chromosomes 14 and 19 (Fig. 2a, arrows), and gain of one copy of chromosome 12 (underlined). The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of an additional translocation between 14q and 18q (Fig. 3a, red arrows, six copies of chromosome 12 are underlined). The remaining fourteen cells contained a normal karyotype. Additionally, FISH studies using BCL3 and IGH break-apart probes confirmed BCL3 and IGH translocations in the first clone (Fig. 2b and c, arrows). With respect to the second clone, IGH;BCL2 dual-fusion probe picked up eight signals for IGH (Fig. 3b, black and white IGH image) which, in combination with karyotype data, was indicative of the presence of eight IGH derivative translocation products. This suggests that all IGH loci are rearranged in the second clone in addition to the near duplication of the chromosome content. BCL2 probe picked up six BCL2 signals (Fig. 3b, black and white BCL2 image) indicating on the presence of four translocated BCL2 loci and two intact BCL2 loci from the non-translocated chromosome 18. Importantly, IGH and BCL2 signals formed four fusions (Fig. 3b, “merge” panel, arrows) confirming two derivative IGH;BCL2 loci on chromosomes 14 and chromosome 18. In addition, IGH break-apart probe confirmed the presence of four translocated IGH loci (Fig. 3b, right panel, four red and four green signals). In summary, first clone was characterized by the IGH;BCL3 translocation event resulting in derivative chromosomes, 14 and 19 (Fig. 4a) and second clone was characterized by the presence of IGH;BCL2 translocation in addition to IGH;BCL3 translocation and near tetraploid chromosome content resulting in four derivative chromosomes 14 and two derivative chromosomes 18 and 19 (Fig. 4b).Fig. 2


Rare double-hit with two translocations involving IGH both, with BCL2 and BCL3, in a monoclonal B-cell lymphoma/leukemia.

Alpatov R, Carstens B, Harding K, Jarrett C, Balakhani S, Lincoln J, Brzeskiewicz P, Guo Y, Ohene-Mobley A, LeRoux J, McDaniel V, Meltesen L, Minka D, Patel M, Manavi C, Swisshelm K - Mol Cytogenet (2015)

a Representative karyotype of the second clone. The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of a translocation between 14q and 18q (IGH;BCL2, red arrows), in addition to a 14q and 19q translocation (IGH;BCL3, white arrows). Six copies of chromosome 12 are underlined. b FISH analysis of the second clone using dual fusion IGH;BCL2 probe (green/red). Black and white image for IGH signal shows 8 loci indicating that all IGH sequences are rearranged and present on derivative chromosomes 14, 18, and 19. Black and white image for BCL2 signal shows 6 loci which represent two intact and two derivative chromosomes 18, and two derivative chromosomes 14. Merged image shows green IGH signals and red BCL2 signals which overlap in four loci, arrows (two copies of derivative chromosome 14 and two copies of derivative chromosome 18). Right panel, IGH break-apart probe (green/red) signal showing four green and four red foci indicative of the presence of four rearranged IGH loci
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: a Representative karyotype of the second clone. The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of a translocation between 14q and 18q (IGH;BCL2, red arrows), in addition to a 14q and 19q translocation (IGH;BCL3, white arrows). Six copies of chromosome 12 are underlined. b FISH analysis of the second clone using dual fusion IGH;BCL2 probe (green/red). Black and white image for IGH signal shows 8 loci indicating that all IGH sequences are rearranged and present on derivative chromosomes 14, 18, and 19. Black and white image for BCL2 signal shows 6 loci which represent two intact and two derivative chromosomes 18, and two derivative chromosomes 14. Merged image shows green IGH signals and red BCL2 signals which overlap in four loci, arrows (two copies of derivative chromosome 14 and two copies of derivative chromosome 18). Right panel, IGH break-apart probe (green/red) signal showing four green and four red foci indicative of the presence of four rearranged IGH loci
Mentions: Cytogenetic studies of bone marrow preparations from this patient revealed two related abnormal clones in eight of twenty-two metaphase spreads examined. The first clone (stemline [sl]), six cells, contained a translocation between the long (q) arm of chromosomes 14 and 19 (Fig. 2a, arrows), and gain of one copy of chromosome 12 (underlined). The second clone, a composite of two cells, was a doubling of the stemline clone (the first clone) with two copies of an additional translocation between 14q and 18q (Fig. 3a, red arrows, six copies of chromosome 12 are underlined). The remaining fourteen cells contained a normal karyotype. Additionally, FISH studies using BCL3 and IGH break-apart probes confirmed BCL3 and IGH translocations in the first clone (Fig. 2b and c, arrows). With respect to the second clone, IGH;BCL2 dual-fusion probe picked up eight signals for IGH (Fig. 3b, black and white IGH image) which, in combination with karyotype data, was indicative of the presence of eight IGH derivative translocation products. This suggests that all IGH loci are rearranged in the second clone in addition to the near duplication of the chromosome content. BCL2 probe picked up six BCL2 signals (Fig. 3b, black and white BCL2 image) indicating on the presence of four translocated BCL2 loci and two intact BCL2 loci from the non-translocated chromosome 18. Importantly, IGH and BCL2 signals formed four fusions (Fig. 3b, “merge” panel, arrows) confirming two derivative IGH;BCL2 loci on chromosomes 14 and chromosome 18. In addition, IGH break-apart probe confirmed the presence of four translocated IGH loci (Fig. 3b, right panel, four red and four green signals). In summary, first clone was characterized by the IGH;BCL3 translocation event resulting in derivative chromosomes, 14 and 19 (Fig. 4a) and second clone was characterized by the presence of IGH;BCL2 translocation in addition to IGH;BCL3 translocation and near tetraploid chromosome content resulting in four derivative chromosomes 14 and two derivative chromosomes 18 and 19 (Fig. 4b).Fig. 2

Bottom Line: Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3.Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

View Article: PubMed Central - PubMed

Affiliation: Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, 3055 Roslyn Street, Suite 200, Denver, CO 80238 USA.

ABSTRACT

Background: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus.

Case presentation: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.

Conclusions: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

No MeSH data available.


Related in: MedlinePlus