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Title: cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia

Abstract

Human leukemic T cells carrying a t(10;14)(q24;q11) chromosome translocation were fused with mouse leukemic T cells, and the hybrids were examined for genetic markers of human chromosomes 10 and 14. Hybrids containing the human 10q+ chromosome had the human genes for terminal deoxynucleotidyltransferase that has been mapped at 10q23-q25 and for C/sub ..cap alpha../ (the constant region of TCRA (the ..cap alpha..-chain locus of the T-cell antigen receptor gene)), but not for V/sub ..cap alpha../ (the variable region of TCRA). Hybrids containing the human 14q- chromosome retained the V/sub ..cap alpha../genes. Thus the 14q11 breakpoint in the t(10;14) chromosome translocation directly involves TCRA, splitting the locus in a region between the V/sub ..cap alpha../ and the C/sub ..cap alpha../ genes. These results suggest that the translocation of the C/sub ..cap alpha../ locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which the authors propose the name TCL3, results in its deregulation, leading to T-cell leukemia. Since hybrids with the 10q+ chromosome also retained the human terminal deoxynucleotidyltransferase gene, it is further concluded that the terminal deoxynucleotidyltransferase locus is proximal to the TCL3 gene, at band 10q23-q24.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Wistar Institute, Philadelphia, PA (USA)
OSTI Identifier:
5316254
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States); Journal Volume: 84:13
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; LEUKEMIA; GENETICS; RECEPTORS; BIOCHEMISTRY; TUMOR CELLS; CHROMOSOMAL ABERRATIONS; HYBRIDIZATION; ANTIGENS; ELECTROPHORESIS; GENE RECOMBINATION; KARYOTYPE; LYMPHOCYTES; MICE; ONCOGENES; PATIENTS; PHOSPHORUS 32; TRANSFERASES; ANIMAL CELLS; ANIMALS; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BIOLOGICAL MATERIALS; BIOLOGY; BLOOD; BLOOD CELLS; BODY FLUIDS; CHEMISTRY; CONNECTIVE TISSUE CELLS; DAYS LIVING RADIOISOTOPES; DISEASES; ENZYMES; GENES; HEMIC DISEASES; ISOTOPES; LEUKOCYTES; LIGHT NUCLEI; MAMMALS; MATERIALS; MEMBRANE PROTEINS; MUTATIONS; NEOPLASMS; NUCLEI; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; PHOSPHORUS ISOTOPES; PROTEINS; RADIOISOTOPES; RODENTS; SOMATIC CELLS; VERTEBRATES; 550401* - Genetics- Tracer Techniques; 550201 - Biochemistry- Tracer Techniques

Citation Formats

Kagan, J., Finan, J., Letofsky, J., Besa, E.C., Nowell, P.C., and Croce, C.M.. cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia. United States: N. p., 1987. Web. doi:10.1073/pnas.84.13.4543.
Kagan, J., Finan, J., Letofsky, J., Besa, E.C., Nowell, P.C., & Croce, C.M.. cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia. United States. doi:10.1073/pnas.84.13.4543.
Kagan, J., Finan, J., Letofsky, J., Besa, E.C., Nowell, P.C., and Croce, C.M.. 1987. "cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia". United States. doi:10.1073/pnas.84.13.4543.
@article{osti_5316254,
title = {cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia},
author = {Kagan, J. and Finan, J. and Letofsky, J. and Besa, E.C. and Nowell, P.C. and Croce, C.M.},
abstractNote = {Human leukemic T cells carrying a t(10;14)(q24;q11) chromosome translocation were fused with mouse leukemic T cells, and the hybrids were examined for genetic markers of human chromosomes 10 and 14. Hybrids containing the human 10q+ chromosome had the human genes for terminal deoxynucleotidyltransferase that has been mapped at 10q23-q25 and for C/sub ..cap alpha../ (the constant region of TCRA (the ..cap alpha..-chain locus of the T-cell antigen receptor gene)), but not for V/sub ..cap alpha../ (the variable region of TCRA). Hybrids containing the human 14q- chromosome retained the V/sub ..cap alpha../genes. Thus the 14q11 breakpoint in the t(10;14) chromosome translocation directly involves TCRA, splitting the locus in a region between the V/sub ..cap alpha../ and the C/sub ..cap alpha../ genes. These results suggest that the translocation of the C/sub ..cap alpha../ locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which the authors propose the name TCL3, results in its deregulation, leading to T-cell leukemia. Since hybrids with the 10q+ chromosome also retained the human terminal deoxynucleotidyltransferase gene, it is further concluded that the terminal deoxynucleotidyltransferase locus is proximal to the TCL3 gene, at band 10q23-q24.},
doi = {10.1073/pnas.84.13.4543},
journal = {Proc. Natl. Acad. Sci. U.S.A.; (United States)},
number = ,
volume = 84:13,
place = {United States},
year = 1987,
month = 7
}
  • The identification of genes located at the breakpoints of chromosomal translocations has been invaluable in determining the pathogenesis of hematogical malignancies. We have investigated the translocation, t(4;11)(q21;p14-15) in a T-ALL patient. Four cases with a similar translocation have been reported; three at diagnosis and one as a secondary cytogenetic change. As a first step towards cloning of the breakpoint sequences, we isolated a somatic cell hybrid containing the der(4) translocation chromosome. The hybrid allowed us to determine the markers flanking the chromosome 11 breakpoint position. The breakpoint was localized to band 11p15.5 between the genes for interferon-like growth factor IImore » (IGF2) and the M1 subunit of ribonucleotide reductase (RRM1) by PCR. Cosmid probes from this region were then used to further localize the breakpoint to a region adjacent to RRM1 by fluorescent in situ hybridization (FISH).« less
  • DNA rearrangements that occurred in the vicinity of T-cell antigen receptor ..beta..-chain gene clusters residing on chromosome 7 were examined in human T-cell acute lymphoblastic leukemia cells. In one patient, it was observed that, for the T-cell receptor ..beta..-chain genes, a D/sub ..beta.. 1/-J/sub ..beta..2.3/ (where D is diversity and J is joining) junction was found on one chromosome, while the other chromosome kept the germ-line configuration. If this D/sub ..beta../-J/sub ..beta../ junction was formed by the customary deletion mechanism, the C/sub ..beta..1/ gene (where C is constant) located between the D/sub ..beta..1/ and J/sub BETA2.3/ loci should have disappearedmore » from this chromosome. The C/sub ..beta..1/ gene indeed was absent from the rearranged chromosome 7, but it was found on chromosome 6 as an inserted segment. The implications of the observations are discussed.« less
  • The authors cloned the translocation-associated and homologous normal MYC alleles from SKW-3, a leukemia T-cell line with the t(8; 14)(q24; q11) translocation, and determined the sequence of the MYC oncogene first exon and flanking 5' putative regulatory regions. S1 nuclease protection experiments utilizing a MYC first exon probe demonstrated transcriptional deregulation of the MYC gene associated with the T-cell receptor ..cap alpha.. locus on the 8q + chromosome of SKW-3 cells. Nucleotide sequence analysis of the translocation-associated (8q +) MYC allele identified a single base substitution within the upstream flanking region; the homologous nontranslocated allele contained an additional substitution andmore » a two-base deletion. None of the deletions or substitutions localized to putative 5' regulatory regions. The MYC first exon sequence was germ line in both alleles. These results demonstrate that alterations within the putative 5' MYC regulatory regions are not necessarily involved in MYC deregulation in T-cell leukemias, and they show that juxtaposition of the T-cell receptor ..cap alpha.. locus to a germ-line MYC oncogene results in MYC deregulation.« less
  • The authors have studied a leukemic stem-cell line, DU.528, that is able to differentiate into myeloid and lymphoid cells. The leukemic cells have a translocation between chromosomes 1 and 14, t(1;14)(p33;q11), which they have molecularly cloned and sequenced. Initial screening used joining (J)-segment probes from the T-cell receptor (TCR) {alpha}- and {delta}-chain loci. In apparent concert with the translocation, a deletion has occurred between {delta}-chain diversity (D)-region genes D{sub {delta}1} and D{sub {delta}2}. The nature of the D{sub {delta}1}-D{sub {delta}2} deletional event implicates a lymphoid recombinase in the mechanism of the translocation. As a consequence of the translocation, an unusualmore » fusion transcript was generated. Probes from chromosome 1 detected a previously unreported transcript in RNA from both the cell line and the patient. A chromosome 14 probe identified the same transcript, thus confirming a fusion transcript derived from both chromosomes 1 and 14. This translocation may identify a gene for which they propose the name SCL (stem-cell leukemia) that is important for hemopoietic development and oncogenesis and that has been disrupted or altered in this stem-cell line.« less
  • Recent molecular analyses of Burkitt lymphomas carrying the t(8;14) chromosome translocation have indicated that a dichotomy exists regarding the molecular mechanisms by which the translocations occur. Most sporadic Burkitt tumors carry translocations that apparently arise due to mistakes in the immunoglobulin isotype-switching process. In contrast, there is evidence that the translocations of most endemic Burkitt lymphomas occur as a consequence of aberrant V-D-J recombination of variable, diversity, and joining gene segments, catalyzed by the recombinase enzymes. This phenomenon was first noted in follicular lymphomas and chronic lymphocytic leukemias of the B-cell lineage and has been described in T-cell malignancies asmore » well. In each of these cases, analysis of the nucleotide sequence at chromosome breakpoints demonstrated the involvement of immunoglobulin heavy chain J/sub H/ or T-cell-receptor ..cap alpha..-chain J..cap alpha.. gene segments in the translocation. The authors now have cloned and sequenced both the 8q- and 14q+ translocation breakpoints deriving from the t(8;14) translocation of the endemic Burkitt lymphoma line Daudi. The data show that the translocation resulted from a reciprocal exchange between the D/sub H/ region on chromosome 14 and sequences far 5' of the MYC protooncogene on chromosome 8. Features of the nucleotide sequences surrounding the breakpoint further implicate the V-D-J joining machinery in the genesis of chromosome translocation in endemic Burkitt lymphomas and, more generally, in other lymphoid malignancies as well.« less