Identification of candidate tumor‐suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms

Steinemann, Doris; Gesk, Stefan; Zhang, Yanming; Harder, Lana; Pilarsky, Christian; Hinzmann, Bernd; Martin-Subero, José Ignacio; Calasanz, Marı́a José; Mungall, Andrew J.; Rosenthal, André; Siebert, Reiner; Schlegelberger, Brigitte

doi:10.1002/gcc.10231

Cited by 37 publications

(30 citation statements)

References 32 publications

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“…56 The regions of minimal common 6q deletion vary with disease type, suggesting that different tumor suppressor genes might be affected in each of these neoplasms. [57][58][59] In BL cell lines these deletions are consistently associated with loss of heterozygosity in the 6q25-27 region. 56 Genes possibly affected by 6q abnormalities include BACH2 (encoding for B-lineage specific transcription factor, a putative tumor suppressor gene), on 6q15, 60,61 and BLIMP1 (B-lymphocyte maturation promoting), on 6q21-q22.1.…”

Section: Discussionmentioning

confidence: 99%

Secondary chromosomal abnormalities predict outcome in pediatric and adult high‐stage Burkitt lymphoma

Onciu

Schlette

Zhou

et al. 2006

Cancer

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Recent studies suggest that the hypodigms representing the two earliest Australopithecus (Au. anamensis and Au. afarensis) form an ancestor‐descendant lineage. Understanding the details of this possible transition is important comparative evidence for assessing the likelihood of other examples of ancestor‐descendant lineages within the hominin clade. To this end we have analyzed crown and cusp base areas of high resolution replicas of the mandibular molars of Au. anamensis (Allia Bay and Kanapoi sites) and those of Au. afarensis (Hadar, Laetoli, and Maka). We found no statistically significant differences in crown areas between these hypodigms although the mean of M1 crowns was smaller in Au. anamensis, being the smallest of any Australopithecus species sampled to date. Intraspecies comparison of the areas of mesial cusps for each molar type using Wilcoxon signed rank test showed no differences for Au. anamensis. Significant differences were found between the protoconid and metaconid of Au. afarensis M2s and M3s. Furthermore, the area formed by the posterior cusps as a whole relative to the anterior cusps showed significant differences in Au. afarensis M1s and in Au. anamensis M2s but no differences were noted for M3s of either taxon. Developmental information derived from microstructural details in enamel shows that M1 crown formation in Au. anamensis is similar to Pan and shorter than in H. sapiens. Taken together, these data suggests that the overall trend in the Au. anamensis‐Au. afarensis transition may have involved a moderate increase in M1 crown areas with relative expansion of distal cusps. Am J Phys Anthropol , 2012. © 2012 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Secondary chromosomal abnormalities predict outcome in pediatric and adult high‐stage Burkitt lymphoma

Onciu

Schlette

Zhou

et al. 2006

Cancer

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“…Both PDCD2 and BCL6 interact with N-CoR/ mSin3A corepressor complexes, which repress transcription by recruiting histone deacetylase (14,25), and PDCD2 has been shown to negatively regulate host cell factor 1, a multidomain protein required for cell cycle progression (25). Human PDCD2 is located on chromosome 6q27, a region where translocations have been reported in acute myelogenous leukemias and where deletions may occur in cutaneous T cell lymphomas, acute lymphoblastic leukemias (23), and non-Hodgkin lymphomas, including follicular B cell lymphoma (26), and it is believed to contain a putative tumor suppressor gene (27,28). Fan et al (29) found that PDCD2 was among several other proapoptosis genes that were expressed in decreased levels in a multidrug-resistant human colon carcinoma cell line.…”

Section: Discussionmentioning

confidence: 99%

Repression of thePDCD2gene by BCL6 and the implications for the pathogenesis of human B and T cell lymphomas

Baron¹,

Zeleznik‐Le

Baron

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The human BCL6 gene on chromosome 3 band q27, which encodes a transcriptional repressor, is implicated in the pathogenesis of human lymphomas, especially the diffuse large B-cell type. We previously identified the human PDCD2 (programmed cell death-2) gene as a target of BCL6 repression. PDCD2 encodes a protein that is expressed in many human tissues, including lymphocytes, and is known to interact with corepressor complexes. We now show that BCL6 can bind directly to the PDCD2 promoter, repressing its transcription. Knockdown of endogenous BCL6 in a human B cell lymphoma line by introduction of small interfering RNA duplexes increases PDCD2 protein expression. Furthermore, there is an inverse relationship between the expression levels of the BCL6 and PDCD2 proteins in the lymphoid tissues of mice overexpressing human BCL6 (high BCL6 levels, minimal PDCD2) and controls (minimal BCL6, high PDCD2) as well as in tissues examined from some human B and T cell lymphomas. These data confirm PDCD2 as a target of BCL6 and support the concept that repression of PDCD2 by BCL6 is likely important in the pathogenesis of certain human lymphomas.human lymphomas ͉ target of BCL6 B CL6, a gene on chromosome 3, band q27, encodes a nuclear zinc finger protein that is a transcriptional repressor (1-3). This protein is expressed at high levels in human lymph node germinal center B cells, most cortical thymocytes, and some human B and T cell lymphomas (4). The BCL6 gene was identified (5-7) through its involvement in chromosomal translocations that occur in Ϸ40% of diffuse large-cell B cell lymphomas. In other lymphomas, mutations occur 5Ј to the BCL6 coding region (8). The BCL6 protein binds DNA in a sequencespecific fashion through its C-terminal zinc finger region (9, 10). It conveys transcriptional repression through an N-terminal POZ domain and a second domain that is more centrally located (1-3, 11) and interacts with a number of corepressors (12)(13)(14). It is thought that the BCL6-repressive effects are mediated through multiprotein repression complexes with histone deacetylase activity. A peptide that specifically binds BCL6 and blocks corepressor recruitment leads to apoptosis and cell-cycle arrest of BCL6-positive lymphoma cells (15). Mice overexpressing human (16) or murine (17) BCL6 develop lymphomas.We previously generated a dominant-negative cell system (18) with the use of a construct expressing the BCL6 zinc fingers, which compete with the binding of endogenous BCL6 in BJAB cells (an Epstein-Barr virus-negative Burkitt lymphoma cell line expressing high levels of BCL6) (19). Because BCL6 is a repressor, competition for binding of the full-length endogenous BCL6 protein by the exogenously transfected zinc fingers results in up-regulation of BCL6 target genes. We used subtractive hybridization techniques to amplify differentially expressed sequences. These studies led to the identification of the PDCD2 (programmed cell death-2) gene as a target of BCL6. Immunohistochemistry performed on human tonsil with antibodies sp...

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“…The results were concordant with the SNP array data in that all three abnormalities were confirmed and no additional regions of allelic imbalance were found (Figure1b and data not shown). Interestingly, loss of 6q material is a frequent aberration in nonHodgkin lymphoma and is also occasionally found in myelodysplastic syndromes (MDS) (Steinemann et al, 2003;Mitelman et al, 2006). Gain of 3q is associated with clonal evolution from Fanconi anemia to MDS (To¨nnies et al, 2003).…”

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confidence: 99%

Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11

et al. 2007

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Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used arraybased comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

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Identification of candidate tumor‐suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms

Cited by 37 publications

References 32 publications

Secondary chromosomal abnormalities predict outcome in pediatric and adult high‐stage Burkitt lymphoma

Secondary chromosomal abnormalities predict outcome in pediatric and adult high‐stage Burkitt lymphoma

Repression of thePDCD2gene by BCL6 and the implications for the pathogenesis of human B and T cell lymphomas

Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11

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