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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A comparative study of the immunohistochemical (Stem cell leukemia/T-cell acute leukemia [SCL/TAL-1] protein expression) and genotypic (deletions in the SCL/tal-1 gene) findings in T-acute lymphoblastic leukemia (T-ALL) is presented. Formalin-fixed tissue from 50 cases of T-ALL were stained with a novel monoclonal antibody, 2TL 242, which recognizes SCL/TAL-1 protein. Twenty-four cases showed nuclear immunolabeling of leukemic cells. Nuclear positivity was not evident in any other type of leukemia or lymphoma tested with the antibody. Genotypic analysis of 25 cases of T-ALL showed a deletion involving the SCL/tal-1 gene in nine cases. These results suggest that protein expression is not dependent on derangement of the SCL/tal-1 gene, because immunohistochemical detection of the protein was noted in the presence and absence of a tal-d1 deletion.
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PMID:SCL/Tal-1 expression in T-acute lymphoblastic leukemia: an immunohistochemical and genotypic study. 767

Activation of the SCL (or TAL-1) gene as a result of chromosomal translocation or deletion is a frequent molecular lesion in acute T-cell leukemia. By virtue of its membership in the basic helix-loop-helix family of transcription factors, the SCL gene is a candidate to regulate events in hematopoietic differentiation. We have used polyclonal antibody raised against a bacterial expressed malE-SCL fusion protein to characterize SCL protein expression in postimplantation embryos and in neonatal and adult mice. SCL protein was detected at day 7.5 post coitum at both embryonic and extraembryonic sites, approximately 24 hours before the formation of recognizable hematopoietic elements. Expression then localized to blood islands of the yolk sac followed by localization to fetal liver and spleen, paralleling the hematopoietic activity of these tissues during development. SCL protein was detected in erythroblasts in fetal and adult spleen, myeloid cells and megakaryocytes in spleen and bone marrow, mast cells in skin, and in rare cells in fetal and adult thymus. In addition, SCL protein was noted in endothelial progenitors in blood islands and in endothelial cells and angioblasts in a number of organs at times coincident with their vascularization. SCL expression was also observed in other nonhematopoietic cell types in the developing skeletal and nervous systems. These results show that SCL expression is one of the earliest markers of mammalian hematopoietic development and are compatible with a role for this transcription factor in terminal differentiation of the erythroid and megakaryocytic lineages. SCL expression by cells in the thymus suggests that the gene may be active at some stage of T-cell differentiation and may be relevant to its involvement by chromosomal rearrangements in T-lymphoid leukemias. Finally, expression of the gene in developing brain, cartilage, and vascular endothelium indicates SCL may have actions in neural development, osteogenesis, and vasculogenesis, as well as in hematopoietic differentiation.
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PMID:The SCL/TAL-1 gene is expressed in progenitors of both the hematopoietic and vascular systems during embryogenesis. 811 24

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.
Leukemia 1993 Aug
PMID:Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. 835 Jun 33

Two types of markers, namely the clone-specific markers including T-cell receptor (TCR) gamma, TCR delta, and Ig heavy-chain (IgH) gene rearrangements, and malignancy-specific fusion gene mRNA such as SIL-TAL-1, BCR-ABL, and HRX-partner genes, were investigated by molecular biology techniques in 65 Chinese patients with acute lymphoblastic leukemia (ALL). In combination, these markers were informative among 96% of patients. Minimal residual disease (MRD) was followed up in 23 of these patients with available materials over a period varying from 8 to 54 months with at least one leukemia-specific probe. In most children, MRD was decreased continuously to an ultimately undetectable level within 6 to 12 months after remission induction therapy. One patient exhibited low-level residual leukemic cells for 4 years before the MRD turned negative. Another patient remained in complete remission for 45 months, although a positive signal was detected at 34 months using TCR delta probe, but was negative with a TCR gamma marker which was positive at presentation. In three patients who relapsed, MRD either persisted through the clinical course or became positive and eventually increased 3-11 months before clinical relapse. These data suggested that the combined use of multiple gene markers is a valuable tool for the PCR-based MRD detection, since it can cover most ALL patients. Furthermore, long-term follow-up of MRD is helpful for determining the dosage as well as the period of maintenance chemotherapy and for predicting impending relapse.
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PMID:Long-term follow-up of minimal residual disease in childhood acute lymphoblastic leukemia patients by polymerase chain reaction analysis of multiple clone-specific or malignancy-specific gene markers. 864 Jul 18

Fifty formalin fixed, paraffin-embedded cases of T-acute lymphoblastic leukaemia (T-ALL) from 12 bone marrow trephines and 38 lymph nodes were stained with a new monoclonal antibody, 2TL 242, raised against recombinant TAL1 protein. The antibody recognizes TAL-1 polypeptides of molecular weight 39 and 41 kD (full length). In addition, a variety of other leukaemias and lymphomas were also stained with 2TL 242. Twenty-four of the 50 cases of T-ALL showed nuclear positivity, ranging from 10 to 90 per cent of leukaemic cells. A positive staining reaction was nuclear and stippled in pattern. Nuclear staining was not seen in any other type of leukaemia or lymphoma. Five cases of follicular lymphoma showed diffuse cytoplasmic staining of variable intensity. Although some background staining is obtained with this antibody, positive nuclear staining is easily distinguishable. This monoclonal antibody has a potential role in primary diagnosis and in the detection of minimal residual disease in T-ALL.
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PMID:An immunohistochemical study of TAL-1 protein expression in leukaemias and lymphomas with a novel monoclonal antibody, 2TL 242. 877 37

The SCL gene (also known as TAL-1) encodes a basic helix-loop-helix transcription factor that is essential for the development of all haematopoietic lineages, and ectopic expression of which results in T cell leukaemia. SCL is expressed in normal pluripotent haematopoietic stem cells and its expression is maintained during differentiation along erythroid, mast and megakaryocytic lineages, but is extinguished following commitment to other cell types. The mechanisms responsible for this pattern of expression are poorly understood, but are likely to illuminate the molecular basis for stem cell development and lineage commitment. We have identified multiple lineage-restricted DNase I hypersensitive sites in a 45 kb region spanning the murine SCL locus. Committed erythroid cells and CD34 positive primitive myeloid cells exhibited both shared and unique DNase I hypersensitive sites whereas none were found in T cells. The function of each hypersensitive site was studied using both transient and stable reporter assays in erythroid, primitive myeloid and T cells. Multiple positive and negative regulatory elements were characterised and found to display lineage-specificity, promoter-specificity and/or chromatin-dependence. These results represent the first description of key components of a complex network of regulatory elements controlling SCL expression during haematopoiesis.
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PMID:Transcription of the SCL gene in erythroid and CD34 positive primitive myeloid cells is controlled by a complex network of lineage-restricted chromatin-dependent and chromatin-independent regulatory elements. 939 38

Despite the major functions of the basic helix-loop-helix transcription factor TAL-1 in hematopoiesis and T-cell leukemogenesis, no TAL-1 target gene has been identified. Using immunoprecipitation of genomic fragments bound to TAL-1 in the chromatin of murine erythro-leukemia (MEL) cells, we found that 10% of the immunoselected fragments contained a CAGATG or a CAGGTG E-box, followed by a GATA site. We studied one of these fragments containing two E-boxes, CAGATG and CAGGTC, followed by a GATA motif, and showed that TAL-1 binds to the CAGGTG E-box with an affinity modulated by the CAGATG or the GATA site, and that the CAGGTG-GATA motif exhibits positive transcriptional activity in MEL but not in HeLa cells. This immunoselected sequence is located within an intron of a new gene co-expressed with TAL-1 in endothelial and erythroid cells, but not expressed in fibroblasts or adult liver where no TAL-1 mRNA was detected. Finally, in vitro differentiation of embryonic stem cells towards the erythro/megakaryocytic pathways showed that the TAL-1 target gene expression followed TAL-1 and GATA-1 expression. These results establish that TAL-1 is likely to activate its target genes through a complex that binds an E-box-GATA motif and define the first gene regulated by TAL-1.
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PMID:Chromatin immunoselection defines a TAL-1 target gene. 972 51

Hematologic relapse remains the greatest obstacle to the cure of children with acute lymphoblastic leukemia (ALL). Recent studies have shown that patients with increased risk of relapse can be identified by measuring residual leukemic cells, called minimal residual disease (MRD), during clinical remission. Current PCR methods, however, for measuring MRD are cumbersome and time-consuming. To improve and simplify MRD assessment, we developed a real-time quantitative PCR (RQ-PCR) assay for detection of leukemic cells that harbor the TAL-1 deletion. We studied serial dilutions of leukemic DNA and found the assay had a sensitivity of detection of one leukemic cell among 100,000 normal cells. We then investigated 23 samples from eight children with ALL in clinical remission. We quantified residual leukemic cells by using the TAL-1 RQ-PCR assay and by using limiting dilution analysis. In 17 samples, both methods detected MRD levels > or =0.001%. The percentages of leukemic cells measured by the two methods correlated well (r2 = 0.926). In the remaining six samples, both methods detected fewer than 0.001% leukemic cells. We conclude the TAL-1 RQ-PCR assay can be used for rapid, sensitive and accurate assessment of MRD in T-lineage ALL with the TAL-1 deletion.
Leukemia 2001 Jan
PMID:Quantification of minimal residual disease in T-lineage acute lymphoblastic leukemia with the TAL-1 deletion using a standardized real-time PCR assay. 1124 85

Activation of the basic helix-loop-helix (bHLH) gene TAL-1 (or SCL) is the most frequent gain-of-function mutation in pediatric T cell acute lymphoblastic leukemia (T-ALL). Similarly, mis-expression of tal-1 in the thymus of transgenic mice results in the development of clonal T cell lymphoblastic leukemia. To determine the mechanism(s) of tal-1-induced leukemogenesis, we created transgenic mice expressing a DNA binding mutant of tal-1. Surprisingly, these mice develop disease, demonstrating that the DNA binding properties of tal-1 are not required to induce leukemia/lymphoma in mice. However, wild type tal-1 and the DNA binding mutant both form stable complexes with E2A proteins. In addition, tal-1 stimulates differentiation of CD8-single positive thymocytes but inhibits the development of CD4-single positive cells: effects also observed in E2A-deficient mice. Our study suggests that the bHLH protein tal-1 contributes to leukemia by interfering with E2A protein function(s).
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PMID:The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice. 1143 53

Acquired chromosomal anomalies (most commonly translocations) in lymphoma and leukemia usually result in either activation of a quiescent gene (by means of immunoglobulin or T-cell-receptor promotors) and expression of an intact protein product, or creation of a fusion gene encoding a chimeric protein. This review summarizes current immunocytochemical studies of these 2 categories of oncogenic protein, with emphasis on the clinical relevance of their detection in diagnostic samples. Among the quiescent genes activated by rearrangement, expression of cyclin D1 (due to rearrangement of the CCND1 [BCL-1] gene) is a near-specific marker of t(11;14) in mantle cell lymphoma; BCL-2 expression distinguishes follicular lymphoma cells from their nonneoplastic counterparts in reactive germinal centers and appears to be an independent prognostic marker in diffuse large cell lymphoma; and TAL-1 (SCL) expression identifies T-cell acute lymphoblastic neoplasms in which this gene is activated. The protein products of other genes activated by chromosomal rearrangement have a role as markers of either lineage (eg, PAX-5 [B-cell-specific activator protein] for B cells, including B-lymphoblastic neoplasms), or maturation stage (eg, BCL-6 for germinal-center and activated B cells and MUM-1/IRF4 for plasma cells). Currently, no hybrid protein encoded by fusion genes is reliably detectable by antibodies recognizing unique junctional epitopes (ie, epitopes absent from the wild-type constituent proteins). Nevertheless, staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RARalpha is highly distinctive. Similarly, antibodies to the anaplastic lymphoma kinase (ALK) tyrosine kinase are valuable (because wild-type ALK is not found in normal lymphoid tissue) in detecting neoplasms (CD30-positive large T-cell lymphomas) with t(2;5) or its variants. Thus, immunocytochemical detection of the products of many rearranged genes in lymphoma and leukemia can be clinically informative and provide information on cellular and subcellular protein expression that cannot be inferred from studies based on messenger RNA.
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PMID:Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. 1178 Dec 20


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