The LCK Gene Is Involved in the t(1;7)(p34;q34) in the T‐Cell Acute Lymphoblastic Leukemia Derived Cell Line, HSB‐2

Burnett, Robert; David, Jean‐Claude; Harden, Alanna M.; Beau, Michelle M. Le; Rowley, Janet D.; Dı́az, Manuel O.

doi:10.1002/gcc.2870030608

Cited by 42 publications

(19 citation statements)

References 27 publications

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“…The t(1;7)(p34;q34) translocation in HSB2 cells removes the distal promoter of LCK from the proximal promoter and replaces sequences 5' to the proximal promoter with the T-cell receptor f constant region enhancer (10). If this translocation is essential to the leukemic phenotype, it might indicate that transcriptional deregulation of LCK is essential to maintain expression of a mutant p56/ck protein.…”

Section: Discussionmentioning

confidence: 99%

“…HSB2 p56ick, nevertheless, exhibits the hallmarks of an activated tyrosine kinase: constitutive autophosphorylation in vivo, excessive substrate phosphorylation, and induction of morphological transformation in fibroblasts. Interestingly, HSB2 cells also contain a t(1;7)(p34;q34) translocation that fuses the proximal promoter of one LCK allele on chromosome 1 with the constant region enhancer of the 1B T-cell receptor from chromosome 7 (10,51 (23), by using either affinity-purified rabbit antibodies against phosphotyrosine (23) or a rabbit anti-p56'ck serum prepared by immunization with a trpE-kck-encoded fusion protein expressed in Escherichia coli (22). Immunoprecipitation of p56c was performed from cells labeled biosynthdtiinally for 16 h with 100 ,uCi 35S-methionine and -cysteine (NEN) or 1 mCi 32P; as described elsewhere (22).…”

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confidence: 99%

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Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia.

1994

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The tyrosine protein kinase p56ick transduces signals important for antigen-induced T-cell The lymphocyte-specific tyrosine protein kinase, p561ck, is expressed predominantly in T cells (13,30,53), where it is physically associated with the T-cell transmembrane proteins CD4 and CD8 (43,45,52). During T-cell activation, CD4 and CD8 bind to the major histocompatibility complex glycoprotein (class II or class I, respectively) on an antigen-presenting cell, bringing p56ick in close physical proximity to the T-cell receptor (16). Binding of the antigen-major histocompatibility complex to CD4 and the T-cell receptor subunits triggers the rapid phosphorylation of a set of T-cell proteins on tyrosine (20). pS6ick is thought to mediate some of these phosphorylations, because the addition of antibodies that cross-link cell surface CD4 induces tyrosine phosphorylation of p56ick and activates its phosphotransferase activity in vitro (19, 27).Genetic evidence likewise indicates that enhancement of T-cell activation by CD4 is mediated through pS6Ick. Deletion of the cytoplasmic domain of CD4 that binds p56 ck abrogates the ability of CD4 to enhance antigen-induced interleukin 2 (IL-2) production in CD4-dependent cells (18,33,46), and T cells expressing activated p56Ik are hypersensitive to stimulation through the T-cell receptor (1) while those lacking functional p56iCk are defective in inducing the transient increase in intracellular free calcium that accompanies antigenic stimulation through the T-cell receptor (48). Therefore, p56 Ck performs a pivotal role in T-cell activation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia.

1994

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“…39). Furthermore, there is ample evidence which implicates the role of genes around the flanking region of the break/fusion points in distinct phenotypes of many hematological disorders [4,[26][27][28][29]41]. For examples, 5p13 deletion is one of the most common regions emerging in acute lymphoblastic leukemia, lymphoblastic lymphoma, acute monoblastic leukemia, acute myleoblastic leukemia with maturation, acute myeloid leukemia, adult T-cell lymphoma/ leukemia, chronic lymphocytic leukemia, etc [4,24,25,[41][42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

“…The rearrangements of no. 7 also occur very frequently concomitant with disruption of TRB@ genes in ALL carrying t(7;9) and such rearrangements activates oncogenes positioned near the breakpoints [26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

“…14) but express surface markers encoded by TRB@ which frequently undergoes physiological gene recombination-rearrangements [17]. In ALL carrying t(7;9), the structural rearrangements usually occur very frequently concomitant with disruption of TRB@ genes and such rearrangements activate oncogenes flanking the breakpoints [26][27][28][29]. In view of these findings, we undertook genomic and molecular analyses to validate the SRIK-NKL cells and answer the central question if their genetic profile may merit a future application in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Genomic analysis of CD8+ NK/T cell line, ‘SRIK-NKL’, with array-based CGH (aCGH), SKY/FISH and molecular mapping

et al. 2008

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We performed aCGH, SKY /FISH, molecular mapping and expression analyses on a permanent CD8+ NK/T cell line, 'SRIK-NKL' established from a lymphoma (ALL) patient, in attempt to define the fundamental genetic profile of its unique NK phenotypes. aCGH revealed hemizygous deletion of 6p containing genes responsible for hematopoietic functions. The SKY demonstrated that a constitutive reciprocal translocation, rcpt(5;14)(p13.2;q11) is a stable marker. Using somatic hybrids containing der(5) derived from SRIK-NKL, we found that the breakpoint in one homologue of no. 5 is located upstream of IL7R and also that the breakpoint in no. 14 is located within TRA@. The FISH analysis using BAC which contains TRA@ and its flanking region further revealed a ~231 kb deletion within 14q11 in the der(5) but not in the normal homologue of no. 14. The RT-PCR analysis detected mRNA for TRA@ transcripts which were extending across, but not including, the deleted region. IL7R was detected at least at mRNA levels. These findings were consistent with the immunological findings that TRA@ and IL7R are both expressed at mRNA levels and TRA@ at cytoplasmic protein levels in SRIK-NKL cells. In addition to rept(5;14), aCGH identified novel copy number abnormalities suggesting that the unique phenotype of the SRIK-NKL cell line is not solely due to the TRA@ rearrangement. These findings provide supportive evidence for the notion that SRIK-NKL cells may be useful for studying not only the function of NK cells but also genetic deregulations associated with leukemiogenesis.

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Distinct mechanisms lead to HPRT gene mutations in leukemic cells

Lin

Perkins

Zhang

et al. 2004

Genes Chromosomes & Cancer

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Leukemias are considered malignant clonal disorders arising from the accumulation of mutations in hematopoietic cells; the majority of these mutations are thought to be acquired somatically. Measurement of mutation frequency (Mf) at the hypoxanthine phosphoribosyltransferase (HPRT) locus has been developed as a method for estimating genomic instability. We investigated the Mf in 16 leukemic cell lines to determine whether these cell lines showed evidence of genomic instability. Although some leukemic cell lines had markedly elevated Mfs, the Mfs at the HPRT locus in leukemic cell lines were not always higher than those of B-lymphoblastoid cell lines and T lymphocytes from normal individuals. We were able to identify the HPRT mutation for 159 of 160 individual HPRT mutants. The HPRT mutations were characterized at a molecular level and classified as either gross chromosomal rearrangements (GCRs) or point mutations, such as single-nucleotide substitutions, insertions, or deletions. With rare exceptions, individual leukemic cell lines showed either point mutations or GCR, but not both. Of note, all the cell lines that primarily showed point mutations are known to be defective in mismatch repair machinery.

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The LCK Gene Is Involved in the t(1;7)(p34;q34) in the T‐Cell Acute Lymphoblastic Leukemia Derived Cell Line, HSB‐2

Cited by 42 publications

References 27 publications

Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia.

Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia.

Genomic analysis of CD8+ NK/T cell line, ‘SRIK-NKL’, with array-based CGH (aCGH), SKY/FISH and molecular mapping

Distinct mechanisms lead to HPRT gene mutations in leukemic cells

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