scholarly journals Sint1, a Common Integration Site in SL3-3-Induced T-Cell Lymphomas, Harbors a Putative Proto-Oncogene with Homology to the Septin Gene Family

2000 ◽  
Vol 74 (5) ◽  
pp. 2161-2168 ◽  
Author(s):  
Annette Balle Sørensen ◽  
Anders H. Lund ◽  
Steen Ethelberg ◽  
Neal G. Copeland ◽  
Nancy A. Jenkins ◽  
...  
Keyword(s):  
T Cell ◽  
Cdna Clone ◽  
Integration Site ◽  
Fusion Partner ◽  
Newborn Mice ◽  
Potent Inducer ◽  
T Cell Lymphomas ◽  
Integration Sites ◽  
Virus Integration ◽  
Provirus Integration

ABSTRACT The murine retrovirus SL3-3 is a potent inducer of T-cell lymphomas when inoculated into susceptible newborn mice. Previously, DNAs from twenty SL3-3-induced tumors were screened by PCR for provirus integration sites. Two out of 20 tumors demonstrated clonal provirus insertion into a common region. This region has now been isolated and characterized. The region, named SL3-3 integration site 1 (Sint1), maps to the distal end of mouse chromosome 11, corresponding to human chromosome 17q25, and may be identical to a mouse mammary tumor virus integration site in a T-cell lymphoma,Pad3. Two overlapping genomic λ clones spanning about 35 kb were isolated and used as a starting point for a search for genes in the neighborhood of the virus integration sites. A genomic fragment was used as a hybridization probe to isolate a 3-kb cDNA clone, the expression of which was upregulated in one of two tumors harboring a provirus in Sint1. The cDNA clone is predicted to encode a protein which shows 97.0% identity to a human septin-like protein encoded by a gene which has been found as a fusion partner gene of MLL in an acute myeloid leukemia with a t(11;17)(q23;q25). Together these findings raise the possibility that a proto-oncogene belonging to the septin family, and located about 15 kb upstream of the provirus integration sites, is involved in murine leukemia virus-induced T-cell lymphomagenesis.

scholarly journals Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels

2020 ◽  
Vol 117 (10) ◽  
pp. 5442-5452 ◽  
Author(s):  
Wenliang Wang ◽  
Maria Fasolino ◽  
Benjamin Cattau ◽  
Naomi Goldman ◽  
Weimin Kong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Integration Site ◽  
Chromatin Accessibility ◽  
Site Analysis ◽  
Car T ◽  
Integration Site Analysis ◽  
Integration Sites ◽  
Lentiviral Integration

Chimeric antigen receptor (CAR)-T immunotherapy has yielded impressive results in several B cell malignancies, establishing itself as a powerful means to redirect the natural properties of T lymphocytes. In this strategy, the T cell genome is modified by the integration of lentiviral vectors encoding CAR that direct tumor cell killing. However, this therapeutic approach is often limited by the extent of CAR-T cell expansion in vivo. A major outstanding question is whether or not CAR-T integration itself enhances the proliferative competence of individual T cells by rewiring their regulatory landscape. To address this question, it is critical to define the identity of an individual CAR-T cell and simultaneously chart where the CAR-T vector integrates into the genome. Here, we report the development of a method called EpiVIA (https://github.com/VahediLab/epiVIA) for the joint profiling of the chromatin accessibility and lentiviral integration site analysis at the population and single-cell levels. We validate our technique in clonal cells with previously defined integration sites and further demonstrate the ability to measure lentiviral integration sites and chromatin accessibility of host and viral genomes at the single-cell resolution in CAR-T cells. We anticipate that EpiVIA will enable the single-cell deconstruction of gene regulation during CAR-T therapy, leading to the discovery of cellular factors associated with durable treatment.

scholarly journals Identification of a new common provirus integration site in gross passage A murine leukemia virus-induced mouse thymoma DNA.

1987 ◽  
Vol 7 (1) ◽  
pp. 512-522 ◽  
Author(s):  
R Villemur ◽  
Y Monczak ◽  
E Rassart ◽  
C Kozak ◽  
P Jolicoeur
Keyword(s):  
T Cell ◽  
Murine Leukemia Virus ◽  
Cell Transformation ◽  
Integration Site ◽  
Leukemia Virus ◽  
Tumor Development ◽  
Mouse Strains ◽  
Mouse Tumor ◽  
Provirus Integration ◽  
Murine Leukemia

The Gross passage A murine leukemia virus (MuLV) induced T-cell leukemia of clonal (or oligoclonal) origin in inoculated mice. To study the role of the integrated proviruses in these tumor cells, we cloned several newly integrated proviruses (with their flanking cellular sequences) from a single tumor in procaryotic vectors. With each of the five clones obtained, a probe was prepared from the cellular sequences flanking the provirus. With one such probe (SS8), we screened several Gross passage A MuLV-induced SIM.S mouse tumor DNAs and found that, in 11 of 40 tumors, a provirus was integrated into a common region designated Gin-1. A 26-kilobase-pair sequence of Gin-1 was cloned from two lambda libraries, and a restriction map was derived. All proviruses were integrated as a cluster in the same orientation within a 5-kilobase-pair region of Gin-1, and most of them had a recombinant structure of the mink cell focus-forming virus type. The frequency of Gin-1 occupancy by provirus was much lower in thymoma induced by other strains of MuLV in other mouse strains. Using somatic-cell hybrid DNAs, we mapped Gin-1 on mouse chromosome 19. Gin-1 was not homologous to 16 known oncogenes and was distinct from the other common regions for provirus integration previously described. Therefore, Gin-1 appears to represent a new common provirus integration region. The integration of a provirus within Gin-1 might be an important event leading to T-cell transformation, and the Gin-1 region might harbor sequences which are involved in tumor development.

scholarly journals Linkage on chromosome 10 of several murine retroviral integration loci associated with leukaemia

2002 ◽  
Vol 83 (4) ◽  
pp. 819-827 ◽  
Author(s):  
Peter Haviernik ◽  
Stephen M. Festin ◽  
Rene Opavsky ◽  
Richard P. Koller ◽  
Nighean I. Barr ◽  
...  
Keyword(s):  
Expressed Sequence Tag ◽  
Integration Site ◽  
Northern Analysis ◽  
Local Alignment ◽  
Chromosome 10 ◽  
Leukaemia Virus ◽  
Retroviral Integration ◽  
T Cell Lymphomas ◽  
Exon Prediction ◽  
Integration Sites

Mml loci have been identified as provirus integration sites among a subset of monocytic tumours induced by murine leukaemia virus (MuLV) infection of BALB/c and DBA/2 mice. These myeloid leukaemias contain a retrovirus integrated on chromosome 10 in proximity to the c-myb locus; however, c-myb expression was not altered. Detailed physical mapping enabled placement of the retroviral integration sites ∼25 kb (Mml1), ∼51 kb (Mml2), and ∼70 kb (Mml3) upstream of the c-myb locus. Furthermore, the Fti1 (fit-1) locus, a common integration site in feline leukaemia virus-induced T cell lymphomas, was mapped upstream of Mml3. Sequence analysis of Mml1, Mml2 and Mml3 loci (39·6, 16·4 and 5·9 kb, respectively) in conjunction with the BLAST (basic local alignment search tool) homology searches against the expressed sequence tag (EST) database and the use of gene/exon prediction programs revealed potential coding sequences that were not confirmed by Northern analysis or RT–PCR. The sequences between c-myb and Fti1, which were shown to include two potential scaffold/matrix attachment regions (S/MARs), are most likely regulatory in nature. An extended search for transcribed sequences far upstream of Mml3 revealed five genes, four of which were expressed in multiple tissues in mice. These genes could not be linked to tumour formation by the virus but their homologous sequences were found on human chromosome 6, thus allowing extension of the syntenic region on mouse chromosome 10 to approximately 250 kb.

scholarly journals The rat leukocyte antigen MRC OX-44 is a member of a new family of cell surface proteins which appear to be involved in growth regulation.

1991 ◽  
Vol 11 (5) ◽  
pp. 2864-2872 ◽  
Author(s):  
A Bellacosa ◽  
P A Lazo ◽  
S E Bear ◽  
P N Tsichlis
Keyword(s):  
T Cell ◽  
Cdna Clone ◽  
Growth Regulation ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cdna Clones ◽  
Rat Tissues ◽  
Leukocyte Antigen ◽  
T Cell Lymphomas ◽  
Gene Coding

Moloney murine leukemia virus (MoMuLV)-induced rat T-cell lymphomas express discrete 1.8-, 2.2-, and 4-kb mRNA transcripts hybridizing under conditions of reduced stringency to a probe derived from a region upstream of the first exon of the Tpl-1/Ets-1 gene. Screening a cDNA library from one rat T-cell lymphoma with this genomic probe yielded 15 cDNA clones which were derived from 10 different genes. One of these genes, defined by the cDNA clone pRcT7a, was expressed as a 1.8-kb mRNA transcript in spleen and thymus but not in other normal rat tissues. Expression of the gene defined by the pRcT7a cDNA clone in a series of MoMuLV-induced rat T-cell lymphomas showed a perfect correlation with the expression of the rat leukocyte antigen MRC OX-44. Because of this observation, the pRcT7a clone was sequenced and it was shown to identify a gene coding for a 219-amino-acid protein. The homology between pRcT7a and the Tpl-1 probe used for its detection mapped within the 3' untranslated region of the pRcT7a cDNA clone. The pRcT7a protein, which exhibits four putative transmembrane regions and three putative glycosylation sites, contains a region which is nearly identical in sequence to a peptide derived from the rat leukocyte antigen MRC OX-44. This finding suggested that the pRcT7a cDNA clone defines the gene coding for OX-44. To confirm this finding, a pRcT7a construct in the retrovirus vector pZipNeo was introduced into the OX-44- T-cell lymphoma line 2788. Immunostaining with the MRC OX-44 monoclonal antibody followed by flow cytometry revealed that following gene transfer, the 2788 cells became OX-44+. Sequence comparisons revealed that pRcT7a/MRC OX-44 is a member of a family of genes which includes the melanoma-specific antigen ME491; the human leukocyte antigen CD37; the protein TAPA-1, which is expressed on the surface of human T cells and appears to be involved in growth regulation; the human gastrointestinal tumor antigen CO-029; and the Schistosoma mansoni-associated antigen Sm23.

scholarly journals Rorγ (Rorc) Is a Common Integration Site in Type B Leukemogenic Virus-Induced T-Cell Lymphomas

2004 ◽  
Vol 78 (9) ◽  
pp. 4943-4946 ◽  
Author(s):  
Dana R. Broussard ◽  
Mary M. Lozano ◽  
Jaquelin P. Dudley
Keyword(s):  
T Cell ◽  
Integration Site ◽  
Type B ◽  
T Cell Lymphomas ◽  
Induced Tumors ◽  
Apoptotic Effects ◽  
Common Integration Site

ABSTRACT The retrovirus type B leukemogenic virus (TBLV) causes T-cell lymphomas in mice. We have identified the Rorγ locus as an integration site in 19% of TBLV-induced tumors. Overexpression of one or more Rorγ isoforms in >77% of the tumors tested may complement apoptotic effects of c-myc overexpression.

scholarly journals Analysis of Wild-Type and Mutant SL3-3 Murine Leukemia Virus Insertions in the c-myc Promoter during Lymphomagenesis Reveals Target Site Hot Spots, Virus-Dependent Patterns, and Frequent Error-Prone Gap Repair

2005 ◽  
Vol 79 (1) ◽  
pp. 67-78 ◽  
Author(s):  
Anne Ahlmann Nielsen ◽  
Annette Balle Sørensen ◽  
Jörg Schmidt ◽  
Finn Skou Pedersen
Keyword(s):  
T Cell ◽  
Hot Spots ◽  
Promoter Region ◽  
Deletion Mutant ◽  
Integration Site ◽  
Consensus Sequence ◽  
Wild Type Virus ◽  
Wild Type ◽  
Newborn Mice ◽  
Murine Leukemia

ABSTRACT The murine leukemia retrovirus SL3-3 induces lymphomas in the T-cell compartment of the hematopoetic system when it is injected into newborn mice of susceptible strains. Previously, our laboratory reported on a deletion mutant of SL3-3 that induces T-cell tumors faster than the wild-type virus (S. Ethelberg, A. B. Sørensen, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:9796-9799, 1997). PCR analyses of proviral integrations in the promoter region of the c-myc proto-oncogene in lymphomas induced by wild-type SL3-3 [SL3-3(wt)] and the enhancer deletion mutant displayed a difference in targeting frequency into this locus. We here report on patterns of proviral insertions into the c-myc promoter region from SL3-3(wt), the faster variant, as well as other enhancer variants from a total of approximately 250 tumors. The analysis reveals (i) several integration site hot spots in the c-myc promoter region, (ii) differences in integration patterns between SL3-3(wt) and enhancer deletion mutant viruses, (iii) a correlation between tumor latency and the number of proviral insertions into the c-myc promoter, and (iv) a [5′-(A/C/G)TA(C/G/T)-3′] integration site consensus sequence. Unexpectedly, about 12% of the sequenced insertions were associated with point mutations in the direct repeat flanking the provirus. Based on these results, we propose a model for error-prone gap repair of host-provirus junctions.

Chromosomal localization of acquired MMTV proviral integration sites in T-cell lymphomas

1998 ◽  
Vol 9 (1) ◽  
pp. 84-85 ◽  
Author(s):  
Lakshmi Rajan ◽  
Christine A. Kozak ◽  
Jaquelin P. Dudley
Keyword(s):  
T Cell ◽  
Chromosomal Localization ◽  
Proviral Integration ◽  
T Cell Lymphomas ◽  
Integration Sites

scholarly journals The c-myc Locus Is a Common Integration Site in Type B Retrovirus-Induced T-Cell Lymphomas

2000 ◽  
Vol 74 (5) ◽  
pp. 2466-2471 ◽  
Author(s):  
Lakshmi Rajan ◽  
Dana Broussard ◽  
Mary Lozano ◽  
Chun G. Lee ◽  
Christine A. Kozak ◽  
...  
Keyword(s):  
T Cell ◽  
Integration Site ◽  
Chromosome 15 ◽  
Type B ◽  
T Cell Lymphomas ◽  
Common Integration Site

ABSTRACT Type B leukemogenic virus (TBLV) induces rapidly appearing T-cell leukemias. TBLV insertions near the c-myc gene were detectable in 2 of 30 tumors tested, whereas 80% of the tumors showed c-myc overexpression. TBLV insertions on chromosome 15 (including a newly identified locus, Pad7) may cause c-myc overexpression by cis-acting effects at a distance.

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