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Chromosomal Translocation (chromosomal + translocation)
Selected AbstractsMass Production of Intergeneric Chromosomal Translocations through Pollen Irradiation of Triticum durum-Haynaldia villosa AmphiploidJOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 11 2007Tong-De Bie Abstract Haynaldia villosa possesses a lot of important agronomic traits and has been a powerful gene resource for wheat improvement. However, only several wheat,H. villosa translocation lines have been reported so far. In this study, we attempted to develop an efficient method for inducing wheat,H. villosa chromosomal translocations. Triticum durum-Haynaldia villosa amphiploid pollen treated with 1 200 rad 60Co-,-rays was pollinated to Triticum aestivum cv. ,Chinese Spring'. Ninety-eight intergeneric translocated chromosomes between T. durum and H. villosa were detected by genomic in situ hybridization in 44 of 61 M1 plants, indicating a translocation occurrence frequency of 72.1%; much higher than ever reported. There were 26, 62 and 10 translocated chromosomes involving whole arm translocations, terminal translocations, and intercarlary translocations, respectively. Of the total 108 breakage-fusion events, 79 involved interstitial regions and 29 involved centric regions. The ratio of small segment terminal translocations (W·W-V) was much higher than that of large segment terminal translocations (W-V·V). All of the M1 plants were self-sterile, and their backcross progeny was all obtained with ,Chinese Spring' as pollen donors. Transmission analysis showed that most of the translocations were transmittable. This study provides a new strategy for rapid mass production of wheat-alien chromosomal translocations, especially terminal translocations that will be more significant for wheat improvement. [source] Primary cutaneous follicle center lymphoma of the arm with a novel chromosomal translocation t(12;21)(q13;q22): A case reportAMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2006Tomislav M. Jelic Abstract We report a reciprocal translocation between the long arms of chromosomes 12 and 21, t(12;21)(q13;q22), in a patient with primary cutaneous follicle center lymphoma. Follicle center lymphoma of the skin and follicle center cell lymphoma of the lymph node are morphologically and immunophenotypically very similar. However, the clinical behavior and prognosis of these tumors are different due to the molecular basis of these malignancies. Follicle center cell lymphoma of the lymph node is determined by the presence of a unique translocation between chromosomes 14 and 18, t(14;18)(q32;q21), BCL-2-JH gene rearrangement, that is not present in primary cutaneous follicle center lymphomas. Chromosomal translocations in the primary skin lymphomas have not been previously reported. We hope that our discovery of a new translocation t(12:21)(q13q22) will encourage further investigation into the molecular basis of this translocation and other cytogenetic abnormalities in primary cutaneous B-cell lymphomas. Am. J. Hematol. 81:448,453, 2006. © 2006 Wiley-Liss, Inc. [source] Aetiology of childhood leukemiaBIOELECTROMAGNETICS, Issue S7 2005Tracy Lightfoot Abstract Leukemia is the most common cancer to affect children, accounting for approximately a third of all childhood cancers. The major morphological subtypes of leukemia, acute lymphoblastic leukemia (ALL), and acute myeloblastic leukemia (AML), are characterized by chromosomal translocations involving over 200 genes including mixed lineage leukemia (MLL), TEL, and AML1. Chromosomal translocations involving the MLL gene at 11q23 are a common feature of infant acute leukemia, found in up to 80% of all cases, and there is strong evidence that rearrangements involving the MLL gene or the TEL-AML1 gene fusion can originate in utero. As with most other cancers, the mechanism by which leukemia arises is likely to involve gene-environment interactions. Accordingly, it is important to identify exposures that cause DNA damage and induce chromosome breaks which are inadequately repaired, ultimately leading to the initiation and disease progression. Exposures acting before birth and early in life has long been thought to be important determinants of leukemia, and the list of suspected chemical, physical, and biological agents continues to increase. Unfortunately, the evidence regarding the majority of suggested exposures is limited and often contradictory, and there are areas, which clearly warrant further investigation in order to further our understanding of the aetiology of childhood leukemia. Bioelectromagnetics Supplement 7:S5,S11, 2005. © 2005 Wiley-Liss, Inc. [source] Role of ancillary techniques in diagnosing and subclassifying non-Hodgkin's lymphomas on fine needle aspiration cytologyCYTOPATHOLOGY, Issue 5 2006P. DeyArticle first published online: 8 SEP 200 Non-Hodgkin's lymphomas (NHL) are tumours of the lymphoid cells. During the process of development of lymphoid cells, neoplasia may evolve at any point. Neoplastic cells usually carry the imprint of cell of origin at the stage of origin. Various types of NHL may have similar morphology with wide variation in origin, immunophenotype and other biological features. Different ancillary laboratory techniques may help to overcome the limitations of morphology in this aspect. The commonly used ancillary techniques in lymphomas are immunocytochemistry (IC), flow cytometry, Southern blot (SB) technique, polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH). In addition, laser scanning cytometry (LSC) and DNA microarray technologies are in the research phase. Various laboratory techniques are used for immunophenotyping, demonstration of monoclonality, identification of chromosomal translocation, assessment of cell kinetics and expression of mRNA in the tumour cells. Flow cytometry helps in rapid immunophenotying of NHL and it has an added advantage over IC in recognizing the co-expression of CD markers. Fine needle aspiration cytology (FNAC) combined with flow immunophenotyping may help us to diagnose and subclassify certain NHLs, such as follicular lymphoma and mantle cell lymphoma, which were previously recognized as pure morphological entities. Loss of morphology is one of the important limitations of flow cytometry. LSC can overcome this limitation by studying morphology along with the immunophenotyping pattern of individual cells. Chromosomal changes in NHL can be identified by SB, PCR and FISH. Molecular diagnosis of NHL helps in diagnosis, subclassification, prognostic assessment and even in planning of therapy. DNA microarray is a relatively newer and promising technology. It gives information about the expression of several thousands of genes in a tumour in a single experiment. In the near future, FNAC combined with ancillary techniques may play a major role in diagnosis, subclassification and management of lymphomas. [source] The myeloid leukemia factor interacts with COP9 signalosome subunit 3 in Drosophila melanogasterFEBS JOURNAL, Issue 3 2008Wakana Sugano The human myeloid leukemia factor 1 (hMLF1) gene was first identified as an NPM,hMLF1 fusion gene produced by chromosomal translocation. In Drosophila, dMLF has been identified as a protein homologous to hMLF1 and hMLF2, which interacts with various factors involved in transcriptional regulation. However, the precise cellular function of dMLF remains unclear. To generate further insights, we first examined the behavior of dMLF protein using an antibody specific to dMLF. Immunostaining analyses showed that dMLF localizes in the nucleus in early embryos and cultured cells. Ectopic expression of dMLF in the developing eye imaginal disc using eyeless-GAL4 driver resulted in a small-eye phenotype and co-expression of cyclin E rescued the small-eye phenotype, suggesting the involvement of dMLF in cell-cycle regulation. We therefore analyzed the molecular mechanism of interactions between dMLF and a dMLF-interacting protein, dCSN3, a subunit of the COP9 signalosome, which regulates multiple signaling and cell-cycle pathways. Biochemical and genetic analyses revealed that dMLF interacts with dCSN3 in vivo and glutathione S -transferase pull-down assays revealed that the PCI domain of the dCSN3 protein is sufficient for this to occur, possibly functioning as a structural scaffold for assembly of the COP9 signalosome complex. From these data we propose the possibility that dMLF plays a negative role in assembly of the COP9 signalosome complex. [source] Structural insight of human DEAD-box protein rck/p54 into its substrate recognition with conformational changesGENES TO CELLS, Issue 4 2006Tsutomu Matsui Human rck/p54, a product of the gene cloned at the breakpoint of t(11; 14) (q23;q32) chromosomal translocation on 11q23 in B-cell lymphoma, is a member of the DEAD-box RNA helicase family. Here, the crystal structure of Nc-rck/p54, the N-terminal core domain of rck/p54, revealed that the P-loop in motif I formed a closed conformation, which was induced by Asn131, a residue unique to the RCK subfamily. It appears that ATP does not bind to the P-loop. The results of dynamic light scattering revealed to ATP-induced conformational change of rck/p54. It was demonstrated that free rck/p54 is a distended molecule in solution, and that the approach between N-terminal core and C-terminal domains for ATP binding would be essential when unwinding RNA. The results from helicase assay using electron micrograph, ATP hydrolytic and luciferase assay showed that c-myc IRES RNA, whose secondary structure regulates IRES-dependant translation, was unwound by rck/p54 and indicated that it is a good substrate for rck/p54. Over-expression of rck/p54 in HeLa cells caused growth inhibition and cell cycle arrest at G2/M with down-regulation of c-myc expression. These findings altogether suggest that rck/p54 may affect the IRES-dependent translation of c-myc even in the cells. [source] Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesisGENES, CHROMOSOMES AND CANCER, Issue 4 2008Malin Ageberg The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated. © 2008 Wiley-Liss, Inc. [source] Chromosome band 16q22-linked familial AML: Exclusion of candidate genes, and possible disease risk modification by NQO1 polymorphismsGENES, CHROMOSOMES AND CANCER, Issue 3 2004Robert Escher Analyses of chromosomal translocation and inversion breakpoints in sporadic acute myeloid leukemias have identified many transcription factors as playing a role in leukemogenesis. Studies of families with a Mendelian predisposition to hematological malignancies have identified the gene coding for the transcription factor RUNX1 as a leukemia-predisposing gene involved in the first steps of leukemogenesis. Using two families, another autosomal dominant familial leukemia locus was linked to chromosome band 16q22 where the CBFB gene maps. Although CBFB forms a core-binding factor transcriptional complex with RUNX1, previous analyses have excluded the CBFB gene as the leukemia-predisposing gene in these families. In the current study, we performed an extended molecular analysis in these families of the four other transcription factor genes in the 16q22 critical region as well as of two other genes with a known association with leukemia. Several previously undescribed but nonpathogenic sequence variants were identified. We demonstrated that the transcription factors E2F4, CTCF, NFATC3, and NFAT5, and the genes coding for NAD(P)H:quinone oxido-reductase 1 (NQO1) and for E-cadherin are not responsible for the leukemia susceptibility in these families. The presence of NQO1 polymorphisms may suggest a role for this gene in disease risk modification in these families. © 2004 Wiley-Liss, Inc. [source] Level of MYC overexpression in pediatric Burkitt's lymphoma is strongly dependent on genomic breakpoint location within the MYC locusGENES, CHROMOSOMES AND CANCER, Issue 2 2004Monika Wilda Increased transcriptional activity of the MYC gene is a characteristic feature of Burkitt's lymphoma. Aberrant MYC expression is caused by (1) chromosomal translocation to one of the loci carrying an immunoglobulin gene, (2) mutation within the translocated allele, (3) loss of the block to transcription elongation, or (4) promoter shift. To investigate the influence of breakpoint locations within the MYC gene on MYC transcript levels, we determined both the precise genomic MYC/IGH breakpoints and the amount of MYC mRNA in 25 samples of pediatric Burkitt's lymphoma with translocation t(8;14)(q24;q32). Patients with breakpoints that were 5, from MYC exon 1 had significantly lower expression of MYC than did patients who had a breakpoint within exon 1 or intron 1 (P < 0.05 and 0.005, respectively). The highest mRNA level of MYC (1,006 copies per 100 copies ABL1) was detected in patients with loss of the first exon and transcription initiation from a cryptic P3 promoter within the first intron of the MYC gene. In contrast, there was no obvious correlation between breakpoint locations within the IgH locus and the amount of MYC mRNA. © 2004 Wiley-Liss, Inc. [source] Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with t(11;20)(p15;q11)GENES, CHROMOSOMES AND CANCER, Issue 1 2003Satsuki Iwase The NUP98 gene is involved in several chromosomal abnormalities associated with acute leukemia. The recurrent t(11;20)(p15;q11) chromosomal translocation results in generation of the NUP98/TOP1 chimeric gene. This abnormality has been observed primarily in therapy-related leukemias, and TOP1/NUP98 transcripts have not been demonstrated. We describe a case of de novo acute myeloid leukemia with t(11;20)(p15;q11), with no known history of exposure to chemicals. The translocation occurred in intron 13 of NUP98 and intron 7 of TOP1, as in the three previously reported cases. The breakpoint in NUP98 was exactly the same as that found in a previously reported case. In addition, a reciprocal TOP1/NUP98 transcript was detected for the first time in our patient. © 2003 Wiley-Liss, Inc. [source] Insertion of MLL sequences into chromosome band 5q31 results in an MLL-AF5Q31 fusion and is a rare but recurrent abnormality associated with infant leukemiaGENES, CHROMOSOMES AND CANCER, Issue 3 2003Ramona Deveney MLL gene rearrangements leading to production of MLL fusion proteins are commonly detected in infant leukemia patients; the most common MLL fusion associated with infant leukemia is the MLL-AF4 fusion. A single case of chromosomal rearrangement leading to production of an MLL fusion with AF5Q31, a gene structurally similar to AF4, has been detected recently in the malignant cells of an infant leukemia patient. We have identified a second case of MLL-AF5Q31 fusion, arising from an insertion of MLL sequences into chromosome 5, also in an infant leukemia patient. Because MLL and AF5Q31 are transcribed in opposite orientations, a simple balanced chromosomal translocation cannot produce a fusion protein, and complex chromosomal rearrangements such as insertions and inversions are required to produce an MLL-AF5Q31 fusion protein. This report demonstrates that chromosomal insertion of MLL sequences is a rare but recurrent abnormality associated with infant leukemia. © 2003 Wiley-Liss, Inc. [source] Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11)GENES, CHROMOSOMES AND CANCER, Issue 4 2003Toshihiko Imamura In this study, we examined a pediatric case of therapy-related myelodysplastic syndrome (tMDS). The symptoms developed 17 months after treatment for acute myeloblastic leukemia (AML, M2 subtype according to the French,American,British [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22). Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ hybridization analysis suggested a rearrangement in the monocytic leukemia zinc finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no partner gene on 2p23 could be identified. To our knowledge, this is the first report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are associated with AML chromosomal abnormalities at t(8;16)(p11;p13), inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account for leukemogenesis occurring through the aberrant regulation of histone acetylation. Through a similar mechanism, we believe that MOZ, fused to an unidentified partner gene at 2p23, may have caused an alteration in histone acetylation, resulting in the development of tMDS in this patient. © 2003 Wiley-Liss, Inc. [source] High sensitivity of chemiluminescent methodology for detection of clonal CDR3 sequences in patients with acute lymphoblastic leukemiaHEMATOLOGICAL ONCOLOGY, Issue 2 2004E. Leal Abstract Detection of minimal residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL) has been achieved using several radioactive labelling methodologies; however, limited information exists about the use of chemiluminescent labelling. Although many malignant disorders are related to cytogenetic alterations, there is not a consistent chromosomal translocation that could serve as a tumour marker for the monitoring of MRD. ALL are derived from B-lymphocytes in 80% of cases. In the early stages of their maturation, the immunoglobulin heavy chain genes (IgH) undergo rearrangements among their V, D, and J segments, giving rise to the Complementary Determining Regions (CDR). Among these, CDR3 is considered unique for each lymphocyte and used as a tumour-specific marker in B-ALL patients. In this study, the CDR3 was labelled with digoxigenin and used as a patient-specific probe to test its sensitivity for further detection of MRD. Fourteen pretreatment samples of bone marrow (BM) or peripheral blood (PB) from B-ALL patients were included. Tumour-specific probes were designed from each clonal product by elimination of the consensus sequences. Ten digoxigenin-labelled probes were hybridized with a mixture of their respective clonal DNA and the polyclonal product from a normal healthy donor, in serial dilutions from 1:1 up to 1:107. A sensitivity range of 1:103,1:106 was obtained, with an average of 1:105. Crossed tests performed in four patients, showed right probe specificity in all cases. We propose that the design of allele-specific probes with chemiluminescent labelling, represents a reliable, sure and sensitive alternative methodology for MRD detection in patients with B-cell lymphoproliferative disorders. Copyright © 2004 John Wiley & Sons, Ltd. [source] The effects of STI571 on antigen presentation of dendritic cells generated from patients with chronic myelogenous leukemiaHEMATOLOGICAL ONCOLOGY, Issue 2 2003Naoko Sato Abstract Chronic myelogenous leukemia is caused by the acquisition of the reciprocal (9;22)(q34;q11) chromosomal translocation in hematopoietic stem cells. The fusion protein showed higher and aberrant tyrosine kinase activity. The inhibition of the tyrosine kinase activity of the protein represents a specific therapeutic strategy for bcr/abl-expressing leukemias. STI571 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the Abl protein tyrosine kinase. In this study, we evaluated the effects of STI571 on antigen presentation of dendritic cells generated from the patients with CML. The data showed that by the addition of STI571 the dendritic cells derived from CML clone showed an increased expression of CD1a, CD83, CD80 and CD86 by flow cytometry analysis and showed more intense abilities of allogeneic antigen presentation by mixed leukocyte culture, compared with the control cells without STI571. Our results suggested that STI571 not only has a direct cytotoxic effect on bcr-abl gene rearranged cells but also an indirect effect associated with increased anti-leukemic immunological function due to an intensified antigen presentation. Copyright © 2003 John Wiley & Sons, Ltd. [source] Cellular stress triggers TEL nuclear export via two genetically separable pathwaysJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Caroline A. Hanson Abstract TEL (translocation ets leukemia, also known as ETV6) is a repressor of transcription that is disrupted by the t(12;21), which is the most frequent chromosomal translocation in pediatric acute lymphocytic leukemia. TEL is modified by SUMOylation, and the lysine (Lys 99) that is conjugated to SUMO is required for TEL nuclear export. In addition, TEL is phosphorylated by p38 kinase, which is activated by cellular stress. Induction of cellular stress reduced the ability of TEL to repress transcription in vitro, but the mechanistic basis of this phenomenon was unclear. In this study, we show that osmotic stress causes re-localization of TEL to the cytoplasm and that p38-mediated phosphorylation of TEL is sufficient for this re-localization. However, impairment of both SUMOylation of Lys 99 and p38-dependent phosphorylation of Ser 257 of TEL were required to impair the re-localization of TEL in response to cellular stress induced by high salt, identifying two separate nuclear export pathways. Thus, alteration of the cellular localization of TEL may be a part of the cellular stress response and re-localization of TEL to the cytoplasm is an important step in the regulation of TEL. J. Cell. Biochem. 104: 488,498, 2008. © 2007 Wiley-Liss, Inc. [source] Richter syndrome in B-cell chronic lymphocytic leukemiaPATHOLOGY INTERNATIONAL, Issue 4 2003Naoya Nakamura Richter syndrome (RS) is well known as a secondary high-grade lymphoma, mostly diffuse large B-cell lymphoma (DLBCL) developed in patients with B-cell chronic lymphocytic leukemia (B-CLL). In this review, we describe clinicopathological, histological, immunophenotypical and genetic findings of RS. The patients with RS, regardless of transformation of pre-existing clone or de novo malignant clone, were resistant to conventional combined chemotherapy and died within months of diagnosis. Molecular techniques can provide convincing results for the clonal relationship of RS to pre-existing B-CLL. When RS carries a same rearrangement band or a same sequence as B-CLL by Southern blotting or nucleotide sequence analyses of immunoglobulin heavy and/or light chain genes, it is suggested to that RS transforms from original B-CLL. These analyses have showed that approximately two-thirds of RS cases evolved from a B-CLL clone. How and where does the B-CLL clone evolve to RS? The genetic alteration of transforming B-CLL clone into RS has been addressed. Abnormalities of chromosomes 11 and 14 were most frequently involved in RS, but non-specific. In addition, RS does not include chromosomal translocation between Ig locus and oncogenes or rearrangements of bcl-6 gene, both of which were found in some de novo DLBCL. Several candidates, such as mutation of p53 gene and abnormalities of cyclin dependent kinase inhibitor, have been proposed to play an important role in the transformation of a part of B-CLL. However, there is still uncertainly as to how B-CLL progresses or develops into RS. [source] Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9pARTHRITIS & RHEUMATISM, Issue 5 2006Haoyang Zhuang Objective Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFN, treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Methods Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFN,4, IFN,, the type I IFN,inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor , were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Results Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti,Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFN,/, (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Conclusion Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFN,/, and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE. [source] Insecticide resistance in the aphid Myzus persicae (Sulzer): chromosome location and epigenetic effects on esterase gene expression in clonal lineagesBIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 1 2003LINDA M. FIELD Insecticide treatment of the aphid Myzus persicae (Sulzer) has led to the evolution of several insecticide resistance mechanisms, including the detoxification of insecticides by elevated esterases. This results from amplification of one of two closely related esterase genes (E4 or FE4) with up to 80 copies in the most resistant aphids. The amplified E4 genes are at a single site linked to a chromosomal translocation and resistance can be unstable. Individuals within a clone lose their elevated esterase and resistant phenotype, a good example of ,clonal variation'. This loss of esterase is accompanied by a loss of the corresponding mRNA but the amplified genes are retained with no detectable sequence differences. However, the expressed E4 genes contain 5-methylcytosine, which is lost at the same time as the genes are turned off. This is in direct contrast with vertebrate genes where DNA methylation causes gene silencing, but it does suggest that the resistant phenotype in M. persicae is under epigenetic control. One hypothesis is that 5-methylcytosine in E4 genes facilitates expression by preventing the production of incorrectly initiated transcripts. It is interesting that we have never detected silencing of amplified FE4 genes, possibly because they are at multiple loci and therefore less likely to be subject to synchronous control. © 2003 The Linnean Society of London. Biological Journal of the Linnean Society, 2003, 79, 107,113. [source] Duplication 8q22.1-q24.1 associated with bipolar disorder and speech delayBIPOLAR DISORDERS, Issue 3 2006JF Macayran Objective:, To report a case of a child with bipolar disorder found to have an unbalanced translocation involving the long arm of chromosome 8, a region that has been previously implicated in genome-wide linkage scans. Case report:, A 7-year-old boy with a complex psychiatric symptom presentation including attention deficits, distractibility, impulsivity, pressured speech, sleep disturbance, aggressive behavior, and hypersexuality diagnosed with bipolar disorder. He also showed evidence of borderline intellectual and adaptive functioning and had mild dysmorphic features with a duplication of distal 8q that arose as an unbalanced chromosomal translocation due to a maternal 15p;8q insertion. Conclusion:, This finding of an unbalanced translocation provides further evidence to support previous linkage studies of a potential causative gene on 8q for bipolar disorder. [source] A new acute lymphoblastic leukaemia cell line BEL-1 with t(4; 11) (q21; q23) chromosomal translocation and a unique aberrant p27kip1 transcriptBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2004Ruoping Tang No abstract is available for this article. [source] Detection by the fluorescence in situ hybridization technique of MYC translocations in paraffin-embedded lymphoma biopsy samplesBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2003Eugenia Haralambieva Summary. The detection of chromosomal translocations by fluorescence in situ hybridization (FISH) is widely performed, but very few studies have attempted to apply this technique to paraffin-embedded routine biopsy samples. We report the analysis of paraffin sections from 36 B-cell lymphoma biopsies for MYC translocation breakpoints by FISH. The probes consisted of multi-YAC constructs that flanked the breakpoint region and that, therefore, separate upon a chromosomal translocation and generate split (or ,segregated') signals (rather than a more ambiguous ,co-localization' pattern, obtained when the two partners in a hybrid gene are detected). The results were assessed by a simple approach that avoids the counting of signal numbers per nucleus and so is appropriate for use in routine practice. A total of 19 of the 36 lymphomas were scored as positive for MYC translocation and this included 16 of the 20 patients in whom classic cytogenetics had shown the presence of the (8;14) translocation (or one of its two variants). We conclude that this two-colour ,split-signal' technique based on breakpoint flanking probes can readily detect chromosomal translocations in paraffin sections. Furthermore, our results suggest that cases categorized as ,atypical Burkitt's/Burkitt-like' lymphoma (at least for adult patients) are heterogeneous with respect to translocations involving the MYC oncogene, as well as immunophenotype and clinical features. [source] Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma,CANCER, Issue 4 2005Dafydd G. Thomas M.D., Ph.D. Abstract BACKGROUND Synovial sarcomas are high-grade soft tissue neoplasms often characterized by a biphasic spindle and epithelioid cell morphology. The majority of synovial sarcomas harbor a specific chromosomal translocation in which the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes (most notably SSX1 and SSX2) at chromosome Xp11. SYT/SSX1 translocations are seen in nearly three times as many synovial sarcomas as SYT/SSX2 translocations. Although the SYT/SSX2 fusion is usually associated with the monophasic disease pattern, the SYT/SSX1 fusion is present in tumors with biphasic or monophasic patterns. The SYT/SSX1 fusion gene is associated with more aggressive tumor growth and poor outcome. Despite advances in the therapy of local disease, distant metastasis remains the predominant cause of death. Accordingly, there is a need for alternate therapies, such as those recently developed against the receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and HER-2/neu. METHODS Archival specimens of synovial sarcoma (n = 38) representing 30 patients were assessed for EGFR and HER-2/neu protein expression by standard immunohistochemical techniques. To validate the immunohistochemistry results, quantitative real-time polymerase chain reaction (Q-PCR) assays using either fresh and/or archival material was performed. The presence of gene amplification was determined by chromogenic in-situ hybridization. RESULTS EGFR and HER-2/neu protein were detected by immunohistochemistry in 21 of 38 (55.3%) and 20 of 38 (52.6%) synovial specimens, respectively. EGFR immunoreactivity showed a granular and membranous pattern, whereas HER-2/neu immunoreactivity demonstrated only a membrane pattern. Coexpression was observed in 13 of 38 specimens (34.2%). HER-2/neu expression by immunohistochemistry in synovial sarcomas was restricted to tumors with the SYT/SSX1 translocations. Of 6 specimens with SSX2 translocation, none (0%) showed HER-2/neu immunoreactivity and 1 (17%) demonstrated EGFR expression. Q-PCR demonstrated the presence of mRNA for EGFR and HER-2/neu in 19 of 30 specimens (63.3%) and 22 of 30 specimens (73.3%), respectively. EGFR and HER-2/neu were expressed at low concentrations compared with the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No evidence of gene amplification was observed. CONCLUSIONS EGFR and HER-2/neu are expressed in the majority of patients with SYT/SSX1 synovial sarcomas, albeit at low levels. Treatment with tyrosine kinase inhibitors may represent appropriate alternate therapy for these patients. Cancer 2005. © 2005 American Cancer Society. [source] Nucleophosmin: A versatile molecule associated with hematological malignanciesCANCER SCIENCE, Issue 10 2006Tomoki Naoe Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmic,nuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the N-terminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. Studies of knock-out mice have revealed new aspects regarding NPM1 as a tumor-suppressor gene. This review focuses on the clinical significance of the NPM1 gene in hematological malignancies and newly discovered roles of NPM associated with oncogenesis. (Cancer Sci 2006; 97: 963,969) [source] Role of AML1/Runx1 in the pathogenesis of hematological malignanciesCANCER SCIENCE, Issue 10 2003Mineo Kurokawa AML1/Runx1, originally identified as a gene located at the breakpoint of the t(8;21) translocation, encodes one of the two subunits forming a heterodimeric transcription factor. AML1 contains a highly evolutionally conserved domain called the Runt domain, responsible for both DNA binding and heterodimerization with the partner protein, CBF,. AML1 is widely expressed in all hematopoietic lineages, and regulates the expression of a variety of hematopoietic genes. Numerous studies have shown that AML is a critical regulator of hematopoietic development. In addition, AML1 and CBF, are frequent targets for chromosomal translocation in human leukemia. Translocations lead to the generation of fusion proteins, which play a causative role for the development of leukemia, primarily by inhibiting AML1 function. Point mutations that impair AML1 function are also associated with familial and sporadic leukemias. Loss of AML1 function is thus implicated in a number of leukemias through multiple pathogenic mechanisms. However, AML1-related translocations or haploinsufficiency of AML1 are not immediately leukemogenic in animal models, suggesting that additional genetic events are required for the development of full-blown leukemia. [source] MUM1/IRF4 Expression Is an Unfavorable Prognostic Factor in B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)CANCER SCIENCE, Issue 6 2002Masato Ito B-Cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL) consists of heterogeneous diseases that are distinguished by morphological, immunophenotypic and molecular features. MUM1 (multiple myeloma oncogene 1) is a protooncogene that is deregulated as a result of (6;14)(p25;q32) chromosomal translocation in multiple myeloma, and is also expressed in a variety of malignant lymphoma entities. We examined the expression of MUM1 in B-CLL/SLL, and found that 2 of 4 B-CLL-derived cell lines and 14 of 29 patients' specimens expressed MUM1 by immunohistochemical analysis. MUM1 expression was not associated with CD38 expression, somatic hypermutation of immunoglobulin heavy chain gene variable region (IgVH), or any other clinical characteristics of the patients. Interestingly, the patients who were positive for MUM1 showed shorter overall survival tunes than those who were negative for MUM1 (50% survival: 22 months vs. 82 months) (P=0.0008, log-rank test). Multivariate analysis by Cox's proportional-hazards regression model showed that MUM1 expression and unmutated IgVH status were independent unfavorable prognostic factors in patients with B-CLL/SLL. These findings suggest that MUM1 expression is a useful prognostic factor in B-CLL/SLL. The biological role and mechanism of action of MUM1 in B-CLL/SLL need to be clarified for the development of therapies for patients with the poor prognostic subtype. [source] The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangementsCLINICAL GENETICS, Issue 4 2010H Kurahashi Kurahashi H, Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS. The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangements. The constitutional t(11;22)(q23;q11) is the most common recurrent non-Robertsonian translocation in humans. The breakpoint sequences of both chromosomes are characterized by several hundred base pairs of palindromic AT-rich repeats (PATRRs). Similar PATRRs have also been identified at the breakpoints of other nonrecurrent translocations, suggesting that PATRR-mediated chromosomal translocation represents one of the universal pathways for gross chromosomal rearrangement in the human genome. We propose that PATRRs have the potential to form cruciform structures through intrastrand-base pairing in single-stranded DNA, creating a source of genomic instability and leading to translocations. Indeed, de novo examples of the t(11;22) are detected at a high frequency in sperm from normal healthy males. This review synthesizes recent data illustrating a novel paradigm for an apparent spermatogenesis-specific translocation mechanism. This observation has important implications pertaining to the predominantly paternal origin of de novo gross chromosomal rearrangements in humans. [source] Submicroscopic familial chromosomal translocation between 7q and 12p mimicking an autosomal dominant holoprosencephaly syndromeCLINICAL GENETICS, Issue 4 2010K Izumi No abstract is available for this article. [source] Disruption of Friend of GATA 2 gene (FOG-2) by a de novo t(8;10) chromosomal translocation is associated with heart defects and gonadal dysgenesisCLINICAL GENETICS, Issue 3 2007P Finelli FOG-2 (Friend of GATA 2) is a transcriptional cofactor able to differentially regulate the expression of GATA-target genes in different promoter contexts. Mouse models evidenced that FOG-2 plays a role in congenital heart disease and normal testis development. In human, while FOG-2 mutations have been identified in sporadic cases of tetralogy of Fallot, no mutations are described to be associated with impaired gonadal function. We here describe a young boy with a balanced t(8;10)(q23.1;q21.1) translocation who was born with congenital secundum-type atrial septal defect and gonadal dysgenesis. Fluorescence in situ hybridization mapped the chromosome 8 translocation breakpoint (bkp) to within the IVS4 of the FOG-2 gene, whereas the chromosome 10 bkp was found to lie in a desert gene region. Quantitative analysis of FOG-2 expression revealed the presence of a truncated transcript but there was no detectable change in the expression of the genes flanking the 10q bkp, thus making it possible to assign the observed clinical phenotype to altered FOG-2 expression. Genetic and clinical analyses provide insights into the signaling pathways by which FOG-2 affects not only cardiac development but also gonadal function and its preservation. [source] Genomic and clinical analyses of 2p24 and 12q13-q14 amplification in alveolar rhabdomyosarcoma: A report from the Children's Oncology GroupGENES, CHROMOSOMES AND CANCER, Issue 8 2009Frederic G. Barr Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer that is related to the skeletal muscle lineage and characterized by recurrent chromosomal translocations. Within the ARMS category, there is clinical and genetic heterogeneity, consistent with the premise that "primary" genetic events collaborate with "secondary" events to give rise to subsets with varying clinical features. Previous studies demonstrated that genomic amplification occurs frequently in ARMS. In the current study, we used oligonucleotide arrays to localize two common amplicons to the 2p24 and 12q13-q14 chromosomal regions. Based on the copy number array data, we sublocalized the minimum common regions of 2p24 and 12q13-q14 amplification to a 0.83 Mb region containing the DDX1 and MYCN genes, and a 0.55 Mb region containing 27 genes, respectively. Using fluorescent in situ hybridization assays to measure copy number of the 2p24 and 12q13-q14 regions in over 100 cases, we detected these amplicons in 13% and 12% of cases, respectively. Comparison with fusion status revealed that 2p24 amplification occurred preferentially in cases positive for PAX3-FOXO1 or PAX7-FOXO1 while 12q13-q14 amplification occurred preferentially in PAX3-FOXO1 -positive cases. Expression studies demonstrated that MYCN was usually overexpressed in cases with 2p24 amplification while multiple genes were overexpressed in cases with 12q13-q14 amplification. Finally, although 2p24 amplification did not have a significant association with clinical outcome, 12q13-q14 amplification was associated with significantly worse failure-free and overall survival that was independent of gene fusion status. © 2009 Wiley-Liss, Inc. [source] Complex chromosome aberrations persist in individuals many years after occupational exposure to densely ionizing radiation: An mFISH studyGENES, CHROMOSOMES AND CANCER, Issue 1 2005M. Prakash Hande Long-lived, sensitive, and specific biomarkers of particular mutagenic agents are much sought after and potentially have broad applications in the fields of cancer biology, epidemiology, and prevention. Many clastogens induce a spectrum of chromosome aberrations, and some of them can be exploited as biomarkers of exposure. Densely ionizing radiation, for example, alpha particle radiation (from radon or plutonium) and neutron radiation, preferentially induces complex chromosome aberrations, which can be detected by the 24-color multifluor fluorescence in situ hybridization (mFISH) technique. We report the detection and quantification of stable complex chromosome aberrations in lymphocytes of healthy former nuclear-weapons workers, who were exposed many years ago to plutonium, gamma rays, or both, at the Mayak weapons complex in Russia. We analyzed peripheral-blood lymphocytes from these individuals for the presence of persistent complex chromosome aberrations. A significantly elevated frequency of complex chromosome translocations was detected in the highly exposed plutonium workers but not in the group exposed only to high doses of gamma radiation. No such differences were found for simple chromosomal aberrations. The results suggest that stable complex chromosomal translocations represent a long-lived, quantitative, low-background biomarker of densely ionizing radiation for human populations exposed many years ago. © 2005 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||