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PubMed1997

Establishment and characterization of a new synovial sarcoma cell line, SN-SY-1: special reference to bcl-2 protein and SYT-SSX1 hybrid transcripts.

We established and characterized a new human synovial sarcoma cell line, SN-SY-1, derived from a monophasic fibrous synovial sarcoma excised from the abdominal wall of a 21-year-old man. We maintained the cell line for over 35 passages in vitro. The SN-SY-1 cells in vitro exhibit spindle and polygonal shapes and join to form an epithelial plaque. SN-SY-1 maintained a consistent karyotype: 46,t(X;18)(p11.2;q11.2), Y, t(6;8) (q13-15;q11-13), the same as that of the primary tumor specimen. RT-PCR assay for chimeric SYT-SSX transcripts followed by digestion with restriction enzymes revealed SYT-SSX1 fusion protein. An immunohistochemical study revealed expression of bcl-2 protein in the SN-SY-1 cell line, in vitro and in vivo. However, DNA analysis showed no rearrangement of the bcl-2 gene, and expression of bcl-2 mRNA was low. Why bcl-2 protein was expressed in this synovial sarcoma was not clarified.

Abdominal Neoplasms↗
PubMed1994

Myelomonocytic crisis with t(5;17) and a p53 mutation in a patient with chronic myelogenous leukemia.

We report a 64-year-old Japanese man with chronic myelogenous leukemia (CML) who expired with myelomonocytic crisis. Cytogenetic analyses of chronic phase (CP) and accelerated phase (AP) cells revealed a Philadelphia chromosome and an isochromosome for the long arm of chromosome 17, i(17q). This karyotype was replaced by another karyotype in blast crisis (BC), resulting in near triploidy with t(5;17) (p15;p11) and loss of chromosome 17 pter-->p11. Interphase fluorescent in situ hybridization studies with a chromosome 17 specific alpha satellite DNA probe confirmed the presence of a clonal change in BC. In addition, single-strand conformation polymorphism analysis and PCR-direct sequencing of BC cells revealed a point mutation at codon 203 of the p53 gene, GTG to GAG (Val to Glu), and loss of the normal allele. In contrast, no alterations of the p53 gene were found in CP and AP cells. Therefore, progression of CML in this patient appeared to be related to loss of 17p, as well as a mutation in the p53 gene.

Alleles↗
PubMed2003

Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2).

Cytogenetic analysis of a pediatric T-cell acute lymphoblastic leukemia (ALL) cell line (HPB-ALL) revealed the cryptic t(5;14)(q35;q32.2), recently found in 15-20% pediatric T-ALL patients, with 5q35 and 14q32.2 breakpoints at 5'-HOX11L2 and 3'-BCL11B, respectively. Expression of both BCL11B, which is hematologically restricted to T cells, and HOX11L2 was detected, whereas adjacent genes at 5q35 (RANBP17) and 14q32 (VRK1, HSU88895) were not dysregulated. Apparently, t(5;14)(q35;q32.2) serves to activate HOX11L2 by juxtaposition with elements downstream of BCL11B, implying a novel dysregulatory mechanism comparable to TCRA/D or IGH juxtaposition. As well as providing molecular cytogenetic documentation of t(5;14) ALL, this report validates HPB-ALL cells for investigating this important new disease entity in vitro.

Chromosome Breakage↗
PubMed2005

Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that usually occurs in children and young adults. Only two cases of AFH with genetic rearrangements have been reported previously; both of these had a FUS-ATF1 fusion gene. We have studied an AFH from a 9-year-old boy whose tumor displayed a t(12;22)(q13;q12) as the sole cytogenetic aberration. FISH,RT-PCR, and sequence analyses revealed an EWSR1-ATF1 fusion gene that has previously been reported in clear cell sarcoma (CCS), a soft tissue sarcoma that is morphologically and clinically distinct from AFH. This study thus has demonstrated that the EWSR1-ATF1 chimera represents a fusion gene that can be associated with different tumor types. Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in CCS has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. The AFH, however, did not express the MITF-M transcript, supporting the theory that MITF-M expression in CCS is a reflection of its cellular origin, rather than a consequence of the presence of an EWSR1-ATF1 fusion protein. Activation of the EWSR1-ATF1 oncogene is probably an early step in the transformation process, but the overall gene expression patterns are likely to vary considerably between AFH and CCS, in keeping with their clinicopathologic differences.

Activating Transcription Factor 1↗
PubMed1993

Characterization of human bone marrow-derived closed circular DNA clones.

Because of interest in mechanisms of recombination involved in chromosomal deletions in neoplastic disease, and their relation to possible rearrangements in normal tissues, we are studying circular DNA molecules from human tissue with a long-term goal of investigating them as possible by-products of physiologically relevant intrachromosomal recombination events. Covalently closed circular (ccc) DNA from human bone marrow was cloned in bacteriophage vectors, and fourteen clones chosen randomly from the cccDNA-derived library were characterized. Five clones originated from chromosome-specific centromeric alpha-satellite DNA; two clones carried highly repetitive sequences probably derived from interspersed repetitive elements; six clones were derived from single-copy chromosome-specific sequences which detected homologous rodent sequences; and one clone (EPM10) was derived from a small chromosome 11-specific sequence family which localized to chromosome regions 11cen and 11q14. Oligonucleotide primers derived from the cccDNA clones were used in polymerase chain reaction studies to show that (1) the EPM10 clone carried the circular junction, (2) several of the single-copy products could be detected in three different bone marrow cccDNA preparations, and (3) the Alu-PCR profile for bone marrow cccDNA showed distinct bands which were similar in four bone marrow cccDNA preparations.

Acute Disease↗
PubMed1987

Lipomas have characteristic structural chromosomal rearrangements of 12q13-q14.

Cytogenetic analysis was performed in 10 consecutive lipomas; 6 had typical benign histology whereas four had foci of atypia. Three tumors had supernumerary ring chromosomes, 6 had different balanced rearrangements, and one had a normal karyotype. Chromosome 12 was involved in 5 of the balanced rearrangements and, although less certainly, in all the ring chromosomes, with breakpoints localized to 12q13 or q14. The other rearranged chromosomes were numbers 2, 3, 7, 8, 11, 17 and 22. These results demonstrate the non-random involvement of chromosomal region 12q13-q14 in benign lipogenic tumors. The combined data from this and previous studies on benign and malignant lipogenic tumors indicate that different levels of cytogenetic specificity exist within this group of neoplasms. We suggest that myxoid liposarcoma development requires the recombination of 2 specific chromosomal bands (12q13 and 16pII), whereas for some types of benign lipogenic tumors structural changes in 12q13-q14 may be sufficient for neoplastic growth.

Aged↗
PubMed1987

Large scale physical mapping in the q27 region of the human X chromosome: the coagulation factor IX gene and the mcf.2 transforming sequence are separated by at most 270 kilobase pairs and are surrounded by several 'HTF islands'.

In spite of the large amount of genetic data obtained on the X chromosome and of the availability of many cloned sequences little is known about the physical map of this chromosome. The construction of large-scale restriction maps is now possible with pulsed field gel methods and data has recently been obtained in the region of band Xq28. We present here results of physical mapping in the Xq27 region, i.e. proximal to the fragile site at Xq27.3 associated with mental retardation, and show physical linkage between the coagulation factor IX gene and the mcf.2 transforming sequence recently localized to Xq27. Our data also indicate partial methylation of some sites in this region, and locate several 'HTF islands', i.e. CpG-rich, unmethylated sequences, containing several sites for 'rare cutter' enzymes, which are believed to be associated with expressed 'housekeeping' genes.

Base Composition↗
PubMed1990

A mouse zinc finger gene which is transiently expressed during spermatogenesis.

Zinc finger proteins are polypeptides with sequence-specific, nucleic acid-binding properties. Substantial evidence has established them as a class of trans-acting molecules with regulatory roles in cellular growth and differentiation. We have screened an 11.5 day post coitum urogenital ridge cDNA library with an oligonucleotide encoding a sequence conserved between a variety of zinc finger proteins. By cDNA cloning and sequencing we show that a novel mouse gene, Zfp-35, encodes a protein with a block of 18 zinc finger domains and an N-terminal region rich in acidic residues. The 2.4 kb mRNA encoding this polypeptide is selectively expressed in adult testis, by comparison with other organs. We have analysed Zfp-35 expression in whole testes of sex-reversed mice, whole testes of prepuberal XY animals, germ cell fractions from XY adult testes and by in situ hybridization to sections from adult XY testes. Our studies show that a considerable increase in expression is restricted to spermatocytes at the pachytene stage of meiotic prophase. These experiments suggest that Zfp-35 may act to control gene activity during this particular stage of spermatogenesis.

Amino Acid Sequence↗
PubMed2001

Genetic lesions and perturbation of chromatin architecture: a road to cell transformation.

Differential gene expression is a rigorously precise procedure that defines the developmental program of cells, tissues, organs, and of the entire organism. The correct execution of this program requires the participation of multiple and complex groups of regulators. In addition to transcription factors, which are key tools in ontogenesis by providing sequential switch of different genes, the structure of the chromatin is a dominant determinant leading to gene expression. Through the novel and insightful work of several investigators, it appears that the architecture of the chromatin spanning the genes can and does influence the efficiency of RNA transcription, and therefore of gene expression. Several new enzymatic complexes have been identified that reversibly modify the chromatin architecture by methylation, phosphorylation, and acetylation of the nucleosomal core proteins. These enzymes are crucial for the proper balance and maintenance of gene expression, and are often the target of mutations and alterations in human cancer. Here, we review briefly the current models proposing how some of these enzymes normally modify the chromatin structure and how their functional disruption leads to inappropriate gene expression and cell transformation.

Acetylation↗
PubMed1993

Sites of transcription of the Müllerian inhibiting substance gene in mouse testis.

We have examined the transcription of Müllerian inhibiting substance (MIS) in testis by the sensitive technique of reverse transcription polymerase chain reaction (RTPCR). A developmental study of testis by this nonquantitative technique showed expression at all postnatal stages, including adults while liver and kidney provided negative controls. Cell separation studies indicated that highly purified interstitial cells, as well as less homogeneous Sertoli cell-enriched and germ cell-enriched fractions, contained RNA for MIS. The transcription of MIS in an interstitial cell type was confirmed by finding MIS mRNA in purified Leydig cells. Inasmuch as the germ cell-enriched fraction contains some Sertoli cells, and XX,Sxra and XX,Sxrb which have germ cell-depleted testes, contain MIS mRNA, a Sertoli cell source remains likely for the seminiferous tubule compartment.

Animals↗
PubMed2006

ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression.

BACKGROUND: The t(17;19)(q21;p13), which occurs in a small subset of acute lymphoblastic leukemias (ALLs) and is associated with a dismal prognosis, creates a chimeric E2A-HLF transcription factor with transforming properties. PROCEDURE: We used representational difference analysis to identify candidate E2A-HLF target genes. Transient transfection assays and an inducible expression model system were then used to evaluate the ability of E2A-HLF to modulate target gene expression. RESULTS: We identified ABCB1 (MDR1, P-glycoprotein) as a gene differentially expressed in ALL cell lines with and without E2A-HLF expression and demonstrated that t(17;19)+ ALL cell lines expressed high levels of ABCB1 protein and had a drug efflux-positive phenotype. Although ABCB1 transcription is regulated by C/EBPbeta via interaction with a DNA response element that shares significant homology with the optimal E2A-HLF binding site, E2A-HLF did not directly activate transcription of reporter genes under control of ABCB1 promoter elements in transient transfection assays. However, ABCB1 expression was induced in a DNA-binding independent manner by E2A-HLF, E2A-PBX1, and truncated E2A polypeptides consisting of those portions of E2A present in leukemic fusion proteins. CONCLUSIONS: E2A-HLF-mediated over-expression of ABCB1 may play a critical role in defining the clinical phenotype of ALLs with a t(17;19), suggesting pharmacologic modulation of ABCB1 activity as a rational therapeutic strategy for this chemotherapy resistant subtype of ALL.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

Genetic alterations in the retinoblastoma protein-related p107 gene in human hematologic malignancies.

Genetic alterations in the p107 gene, a close relative of the retinoblastoma tumor suppressor gene, have never been identified in human malignancies. When we searched for such alterations in human hematologic malignancies by Southern blot analysis, 2 of 21 cell lines and 1 of 88 primary disorders had genomic alterations within the gene. Particularly, an altered p107 gene in a diffuse-large B-cell lymphoma cell line, KAL-1, harbored an intragenic deletion of about 15 kbp leading to the expression of an altered p107 mRNA devoid of 819 nucleotides of the coding sequences, which predicts to encode an approximately 87-kDa protein. This cell line was found to express solely a p107 derivative of 84 kDa by immunoblotting analysis. These results suggest that alterations in the p107 gene are probably related to a limited subset of human hematologic malignancies.

Gene Deletion↗
PubMed2000

Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia.

Rearrangements affecting chromosome band 3q21 are observed in a subgroup of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, little is known about the molecular consequences of such aberrations. We therefore established a PAC contig in the 3q21 breakpoint region and identified potential protein coding sequences by exon trapping. One of the exons isolated was from the human GATA-2 gene, which we showed to be transcribed from telomere to centromere. The majority of 3q21 breakpoints are located telomeric to the transcribed portion of this gene in a region that in mice appears to be necessary for proper promoter function. Results of GATA-2 expression analyses in leukemic cell lines as well as primary patient samples are compatible with the hypothesis that 3q21 aberrations contribute to leukemogenesis through deregulation of the hematopoietic transcription factor GATA-2.

Acute Disease↗
PubMed1993

Gametic imprinting as a speciation mechanism in mammals.

Gametic imprinting renders mammalian male and female genomes functionally hemizygous at specific loci. Successful embryogenesis can only be accomplished in the presence of both parental genomes. The mechanism of gametic imprinting is at present unknown, although circumstantial evidence suggests it is similar in nature to X inactivation. A model is presented which describes the effects of switching the imprint pattern at male and female target genes. The consequence of such an event is reproductive isolation, and could lead to the formation of a new species.

Animals↗
PubMed1999

Retinoid receptors in health and disease: co-regulators and the chromatin connection.

Retinoid receptors behave as ligand-dependent transcriptional regulators, repressing transcription in the absence of ligand and activating transcription in its presence. The different effects on transcription are carried out through recruitment of co-regulators: unliganded receptors bind corepressors (NCoR and SMRT) that are found within a complex containing histone deacetylase (HDAC) activity, whereas liganded receptors recruit coactivators with histone acetylase activity (HATs). Chromatin remodeling activities have also shown to be required, suggesting a hierarchy of promoter structure modifications in RA target genes carried out by multiple coregulatory complexes. In this review, we examine the experimental evidence for the model just sketched. We focus on recent findings highlighting new molecular details in receptor-coregulator interactions, including the discovery and initial characterisation of novel complexes with multiple chromatin modifying activities. Finally, we look at the role of aberrant recruitment of the NCoRHDAC complex by altered retinoid receptors in the pathogenesis of acute promyelocytic leukemia. These results point to a crucial role for control of transcription factor coregulator interactions in the regulation of cellular processes, and suggest new molecular targets for cancer therapy.

Acetylation↗
PubMed2001

Molecular, cytogenetic and genetic abnormalities in MDS and secondary AML.

Myelodysplasia (MDS) is a clonal disease, which increases with age, suggesting that multiple steps are required for the evolution of the condition. Approximately 30% of MDS evolve into acute myelogenous leukemia (AML). In this review, we intend to delineate the genetic events, which may drive this sequence and therefore we will focus primarily on cytogenetic abnormalities where the genes have been identified and oncogenes and suppressor genes that have been implicated. In terms of the biological mechanisms, which characterise this process, it is generally thought that the MDS cell has impaired differentiation, and has increased apoptosis. As the disease progresses in addition, the cells have increased proliferation. As the disease evolves, the population of cells, which predominate remain immature, have decreased apoptosis and in many cases, upregulate anti-apoptotic genes and have deregulated proliferation as the number of blast cells increase. Etiological factors, which contribute to the development of leukemia, include therapeutic agents administered for a primary malignancy. The cytogenetic abnormalities, predisposition factors and genes involved in secondary leukemia will also be reviewed.

Acute Disease↗