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

The genetic sequence of the third complementarity determining region (CDR III) of the immunoglobulin heavy chain (IgH) gene was analysed in 55 rearranged alleles from 36 children presenting with B-lineage acute lymphoblastic leukaemia (ALL). This confirmed the unique nature of these rearrangements. However, contrary to the hypothesis that the CDR III is produced by a random process of rearrangement, biased utilisation of diversity (D) segments and of joining (J) regions 4, 5 and 6 was demonstrated. Moreover, preferred sequence boundaries were seen in J regions 1 to 5 and were suggested at the 3'-end of certain D regions, notably D21/9 and DK1. Similar patterns of rearrangement have been noted in normal B-lymphocyte clones. Together with relatively limited N nucleotide addition, these factors may restrict the potential sequence variability at the D-N-J junction. The occurrence of clonal progression by secondary gene rearrangements, such as V-V replacement, favours the use of this site when designing clone-specific oligonucleotide probes for use in monitoring minimal residual disease (MRD). In cases where biased features of D-J rearrangement are shared by both the leukaemic and normal B-lymphocyte clones this could reduce the sensitivity of these probes in detecting low levels of residual disease.
Leukemia 1992 Nov
PMID:Third complementarity determining region (CDR III) sequence analysis in childhood B-lineage acute lymphoblastic leukaemia: implications for the design of oligonucleotide probes for use in monitoring minimal residual disease. 143 6

Patients with kappa L chain expressing chronic lymphocytic leukemia (CLL) frequently have leukemia cells reactive with a murine mAb, designated 17.109. Raised against a monoclonal IgM rheumatoid factor autoantibody, this mAb recognizes a major kappa-L chain-associated cross reactive Id, designated 17.109-CRI. Molecular studies reveal that the 17.109-CRI in CLL is a serologic marker for expression of a conserved kappa L chain V region gene (V Kappa gene) of the V Kappa 3 subgroup, designated Humkv325. We isolated an upstream gene fragment of Humkv325 to examine for Ig gene rearrangements of this and other closely related V Kappa 3 genes by Southern analyses. Consistent with Humkv325 encoding the 17.109-CRI, we find that the genomic DNA from all 17.109-reactive leukemia cell populations have gene rearrangements that are detected using this probe. In addition, we observe V Kappa 3 gene rearrangements frequently in the genomic DNA of lambda L chain-expressing leukemia cells. Of the genomic DNA from 33 lambda-L chain-expressing CLL samples, 8 (24%) had additional nongerm-line bands detected with the Humkv325 probe. Consistent with these bands representing Ig gene rearrangements, the additional band in each but one sample also hybridized with probes specific for the J Kappa region and/or the kappa-deleting element. Using the polymerase chain reaction (PCR), we examined the genomic DNA from all lambda L chain-expressing CLL for V Kappa 3 gene rearrangements to J Kappa and/or Kde. PCR on each DNA sample with V Kappa 3 gene rearrangements detected by Southern analysis generated gene fragments that hybridized specifically with oligonucleotides corresponding to framework or CDR of the Humkv325 gene. Nucleic acid sequence analyses of representative samples confirmed that these DNA contained abortive Humkv325 gene rearrangements. PCR for rearranged V Kappa 3 genes in the DNA of other lambda-L chain-expressing CLL either did not generate any PCR product or produced fragments that failed to hybridize with all Humkv325 oligonucleotide probes. Nucleic acid sequence analyses of the latter demonstrated that these represent abortive V Kappa gene rearrangements involving another conserved V Kappa 3 gene, designated Vg. These studies indicate that Humkv325 and Vg frequently may undergo Ig gene rearrangement independent of their expression. As such, the frequent use of Humkv325 in CLL may be secondary, in part, to an enhanced propensity of this V Kappa 3 gene to undergo genetic rearrangement during B cell ontogeny.
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PMID:Autoantibody-encoding kappa L chain genes frequently rearranged in lambda L chain-expressing chronic lymphocytic leukemia. 190 4

The epidemiology of infection with human T cell leukaemia/lymphoma virus (HTLV) types I and II in England and Wales between 1986 and 1992 has been studied. Two sources of data have been reviewed: reports of cases of infection received by the PHLS Communicable Disease Surveillance Centre, and information about people infected with HTLV-I and II provided on laboratory request forms sent to the Virus Reference Division of the PHLS Central Public Health Laboratory. Most patients were of Caribbean origin. The age and sex distribution of people with disease associated with HTLV-I and II in England and Wales resembles that previously recorded in the Caribbean. The data suggest that the prevalence of disease associated with HTLV infection is low in England and Wales, but case ascertainment may be incomplete.
Commun Dis Rep CDR Rev 1994 May 27
PMID:Surveillance of HTLV infection in England and Wales: 1986-1992. 751 14

Fluorescence in situ hybridization (FISH) and/or RNA-based polymerase chain reaction (RT-PCR) were used to analyze the breakpoints within the AML1 gene and the AML1 fusion transcripts in t(8;21) acute myeloid leukemia (AML). Twenty-two patients presented with the simple t(8;21)(q22;q22) and one with a complex variant t(8;2;16;21). In eight cases we used FISH with AML1 cosmid probes on metaphase chromosomes as well as RT-PCR to detect the junctions of MAL1/CDR (ETO,MTG8). Five cases were analyzed by FISH alone and ten cases by RT-PCR alone. By FISH we could identify three groups according to the distribution of the fluorescent signal. Signals were found in group 1 on chromosomes 21 and 21q+, in group 2 on chromosomes 21, 21q+ and 8q- and in group 3 on chromosomes 21 and 8q-. In all groups we could detect an identical AML1/CDR fusion transcript. This transcript showed splicing of AML1 exon 5 onto CDR. Thus regardless of the heterogeneity suggested by FISH, all the breakpoints in the AML1 gene were clustered in the same intro between exons 5 and 6. Our results bring to over one hundred the number of t(8;21) cases in which an identical translocation could be detected at molecular level by RT-PCR. The high sensitivity of the technique makes it suitable for the diagnosis of this translocation in different stages of the disease. The impact of the molecular detection of t(8;21) cells in clinical remission as far as the treatment and the management of the disease are concerned deserves further discussion.
Leukemia 1995 Feb
PMID:Identical fusion transcript associated with different breakpoints in the AML1 gene in simple and variant t(8;21) acute myeloid leukemia. 786 65

We sequentially analyzed minimal residual disease (MRD) in 7 children with common acute lymphoblastic leukemia (cALL) after autologous bone marrow transplantation (ABMT) with ex vivo purging followed by systemic interleukin-2 infusion. After ABMT, 3 of the 7 patients remained in complete remission (CR) for more than 1 year, and 4 subsequently relapsed. MRD was estimated by polymerase chain reaction amplification to detect the leukemia clone-specific immunoglobulin heavy chain third complementarity determining region (IgH CDR-III). The IgH CDR-III sequences from the relapsed patients were identical with those determined at each respective initial diagnosis. In 2 patients, the levels of MRD were 10(-2) and 10(-5) in the harvested bone marrow (BM) cells, and even after purging the levels were 10(-4) and 10(-5) cells, respectively. One of the 2 patients relapsed 3 months after ABMT, while the other remained in CR for 33 months after ABMT. Among the 4 patients who subsequently relapsed after ABMT, MRD was not detected in the BM samples even 1 month before relapse. Our results suggest that PCR-negativity does not necessarily indicate a lower risk of subsequent relapse. Detection of MRD tends to favor the assessment of the therapeutic effects rather than prediction of relapse.
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PMID:Detection of minimal residual disease in patients with childhood common acute lymphoblastic leukemia after autologous bone marrow transplantation with ex vivo purging and systemic IL-2 infusion: unsuccessful prediction of subsequent relapse. 853 17

AML1, a gene encoding a protein of the PEBP2/CBF family of transcription factors is disrupted by translocations associated with human leukemia. In the t(8;21) acute myelogenous leukemia (AML), AML1 was found fused to a gene on chromosome 8 that we designated CDR (also known as ETO and MTG8). Immunoprecipitation experiments followed by immunoblotting using a combination of antibodies against different epitopes of one of the predicted chimeric proteins encoded by a fully characterized fusion transcript enabled us to visualize a chimeric protein in the t(8;21) Kasumi-1 cell line. The estimated size of this protein is 64 kDa. Immunoblotting of leukemic blasts containing the t(8;21) detected a protein of the same size. Immunofluorescence experiments indicate that the chimeric protein is localized in the nucleus. A normal AML1 protein of 27 kDa was also detected in t(8;21) Kasumi-1 cells. It remains to be established by which mechanism the mutant AML1 isoform may contribute to the leukemogenesis process of t(8;21)-positive acute myeloid leukemia.
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PMID:Detection and subcellular localization of an AML1 chimeric protein in the t(8;21) positive acute myeloid leukemia. 857 Feb 22

Until recently, it was impossible to identify leukemia cells making up less than 1% of a bone marrow sample, which is designated as minimal residual disease (MRD). Owing to the development of the polymerase chain reaction (PCR) MRD can be detected at the 10(-5) level by amplifying the leukemia-specific DNA rearrangement (BCR/ABL, PML/RARA etc.) or clone-specific DNA sequences (IgH chain CDR-III etc.). Here, our studies on MRD of acute lymphoblastic leukemia and acute promyelocytic leukemia are presented, and their technical problems and clinical significance are discussed.
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PMID:[Detection of minimal residual leukemia using polymerase chain reaction method]. 875 31

We applied a simple polymerase chain reaction (PCR) based method for detecting immunoglobulin heavy-chain (IgH) gene rearrangement, using its CDR-III region to assess B-cell clonality in a series of 100 acute lymphoblastic leukemias (ALL) (84 B-cell lineage, 4 null-ALL and 12 T-ALL). The amplified CDR-III regions can be generated in all the B-lineage ALL and separated by size by polyacrylamide gel electrophoresis (PAGE), thereby providing a specific diagnostic marker for each B cell clone. Size heterogeneity resulting from independent IgH rearrangement events and the high resolution power after electrophoresis and silver staining of the PAGE gels can be used to generate a "fingerprint" of the PCR fragments representing either the spectrum of B-cell clonality in complex populations of B lymphocytes or the partially genomic configuration of the VH-N-DH-N-JH region. At diagnosis, we found the presence of one clonal IgH heavy-chain gene rearrangement in 80 B-cell lineage and null ALL and a biclonal rearrangement in 8 cases. The CDR-III bands were of sizes ranging from 80 to 130 bp. The PCR analysis of the IgH gene enabled us to obtain a CDR-III leukemia specific product in all cases, thereby providing a specific and diagnostic marker for each B-cell clone.
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PMID:Amplification of third-complementary-determining-region (CDR-III) of heavy chain immunoglobulin gene (IgH) in one hundred adult acute leukemias. 925 Jul 98

The translocation (8;21) is a chromosome abnormality associated with acute myeloid leukemia (AML). As a consequence of the translocation the AML1 (CBFA2) gene in the 21q22 region is fused to the ETO(CDR,MTG8) gene in the 8q22 region, resulting in one transcriptionally active gene on the 8q- derivative chromosome. In this report we demonstrate the use of a highly specific dual-colour FISH method for the detection of t(8;21) on interphase cells. Genomic probes able to detect the chimeric AML1/ETO gene on the 8q- derivative chromosome were assayed on both normal and leukemic bone marrow and peripheral blood samples. Cut-off values were established by independent analysis of 15 bone marrow specimens negative for the translocation. The cut-off value of positive nuclei was determined to be 2% and the cut-off value for both positive nuclei and nuclei of uncertain classification, 4%. Persistence of cells above these cut-off values was interpreted as persistence of the mutated clone. A total of 36 samples at different disease stages were tested. Interphase cytogenetics detected the translocation at the onset and relapse in the BM or the PB of 14 AML patients with t(8;21). The technique appears to be an alternative tool to both conventional cytogenetics and reverse transcription polymerase chain reaction (RT-PCR) for the monitoring of disease during patients' follow-up. By enabling the analysis of individual cells, interphase FISH is ideal for clonality studies both for clinical and experimental applications.
Leukemia 1998 Jan
PMID:Development of an interphase fluorescent in situ hybridization (FISH) test to detect t(8;21) in AML patients. 943 27

The AML1-CBFbeta transcription factor complex is essential for the definitive hematopoiesis of all lineages and is the most frequent target of chromosomal rearrangements in human leukemia. In the t(8;21) translocation associated with acute myeloid leukemia (AML), the AML1(CBFA2/PEBP2alphaB) gene is juxtaposed to the MTG8(ETO/CDR) gene. We show here that the resultant AML1-MTG8 gene product specifically and strongly interacts with an 85-kDa phosphoprotein. Molecular cloning of cDNA indicated that the AML1-MTG8-binding protein (MTGR1) is highly related to MTG8 and similar to Drosophila Nervy. Comparison of amino acid sequences among MTGR1, MTG8, and Nervy revealed four evolutionarily conserved regions (NHR1 to NHR4). Ectopic expression of AML1-MTG8 in L-G murine myeloid progenitor cells inhibits differentiation to mature neutrophils and induces cell proliferation in response to granulocyte colony-stimulating factor (G-CSF). Analysis with C-terminal deletion mutants of AML1-MTG8 indicated that the region of 51 residues (488 to 538), which contains NHR2, is essential for the induction of G-CSF-dependent cell proliferation. Immunoprecipitation analysis indicates that this region is required for AML1-MTG8 to form a stable complex with MTGR1. Overexpression of MTGR1 stimulates AML1-MTG8 to induce G-CSF-dependent proliferation of L-G cells and to interfere with AML1-dependent transcription. These results suggest that AML1-MTG8 could function as a complex with MTGR1 and that the complex might be important in promoting leukemogenesis.
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PMID:The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1. 944 81


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