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

Mantle cell lymphoma represent a clinicopathologically distinct entity of malignant non-Hodgkin's lymphoma (NHL) and are characterized by a specific chromosomal translocation t(11;14)(q13;q32) involving the cyclin D1 gene also designated as bcl-1/PRAD1 gene on chromosome 11 and the heavy chain immunoglobulin joining region on chromosome 14. We have established a PCR method to amplify t(11;14) junctional sequences in DNA from fresh frozen and paraffin-embedded tissue by bcl-1-specific primers in combination with a consensus immunoglobulin JH primer. A total of 65 cases histologically classified as mantle cell lymphoma (MCL) were analyzed for the presence of a t(11;14) translocation and monoclonal IgH-CDR3 rearrangements. From 26 patients with classical MCL and three cases with the anaplastic variant of MCL fresh frozen biopsy material was available for DNA extraction. We detected a bcl-1/JH rearrangement in 12 out of 29 samples (41%). In 36 cases paraffin-embedded lymph node tissue was the only source of DNA. In this material we found a bcl-1/JH rearrangement in six out of 31 samples with intact DNA (20%). To confirm the specificity of the PCR and to determine the bcl-1/JH junctional region sequences as clone-specific marker in individual patients we characterized the junctional DNA sequences by direct PCR sequencing in 16 cases. Interestingly we found that six bcl-1/JH junctions harbored DH segments in their N regions indicating that bcl-1/JH rearrangements can occur in a later stage of B cell ontogeny during which the complete VH to DH-JH joining or VH-replacement takes place. To investigate the suitability of IgH-CDR3 as sensitive molecular marker for those MCL patients in which a t(11;14) translocation can not easily be amplified, we additionally analysed 60 cases for the presence of monoclonally rearranged IgH genes by IgH-CDR3-PCR. A monoclonal IgH-CDR3 PCR product could be identified in 24 out of 29 fresh frozen samples (79%) whereas only 11 out of 31 samples (36%) with paraffin-derived DNA were positive. We demonstrate that automated fluorescence detection of monoclonal IgH-CDR3 PCR products allows the rapid and sensitive monitoring of minimal residual disease also in cases that lack a PCR amplifiable t(11;14) translocation. In combination with allele-specific primers the procedure may improve current experimental approaches for detection of occult MCL cells at initial staging and residual disease during and after therapy.
Leukemia 1998 Oct
PMID:Structure of Bcl-1 and IgH-CDR3 rearrangements as clonal markers in mantle cell lymphomas. 976 10

Minimal residual disease (MRD) detection in B cell non-Hodgkin's lymphoma (NHL) patients has been shown to be possible using the rearranged heavy (IgH) chain gene as a tumor marker. To explore a second independent tumor marker, we used specific PCR primer sets to identify tumor-specific rearranged Ig light chain (IgL) genes. Rearranged IgL genes were amplified from lymphoma DNA by multiplex PCR using separate primer sets for the Igkappa and the Iglambda genes. They were considered to be of tumor origin if they were monoclonal, and if the same rearrangement was isolated from at least two independent PCR products. From 12 out of 13 intermediate- and high-grade malignant NHL, PCR products could be obtained with IgL specific primers. PCR products from five NHL were studied in detail by cloning and sequencing. The rearranged IgL genes showed 85-100% homology with their closest germ line counterparts. Intraclonal IgL sequence heterogeneity was studied in five lymphomas and detected in only one. Minimal disease was studied in three patients by PCR, followed by Southern hybridization of the PCR product with a lymphoma-specific oligonucleotide probe, which allowed for detection of lymphoma DNA following 1000-fold dilution. Blood samples from one patient, who is in long-term clinical remission, were negative for the lymphoma-specific rearranged Igkappa gene. In the second patient the rearranged Iglambda gene was detected during the first clinical remission, that was followed by a nodal relapse, but not during the second remission, that has been stable for almost 3 years now. The third patient was negative for the rearranged Iglambda gene in blood samples up to 102 months after diagnosis. Circulating lymphoma cells were detected in blood and bone marrow samples which were negative by morphological and immunological criteria. Our studies show that the rearranged IgL gene can be used as a second independent tumor marker in intermediate- and high-grade malignant NHL.
Leukemia 1998 Nov
PMID:Rearranged immunoglobulin light chain genes as minimal residual disease markers in intermediate- and high-grade malignant B cell non-Hodgkin's lymphoma. 982 58

Splenic marginal zone lymphomas (MZLs) have been found to occur at a high frequency in NFS.N mice congenic for high-expressing ecotropic murine leukemia virus (MuLV) genes from AKR and C58 mice. Based on morphological, immunological, and molecular studies of these mice, MZL is clearly recognizable as a distinct disease with a characteristic clinical behavior. MZL was staged according to the degree of accumulation and morphological change of cells within the splenic marginal zone, as follows: 1) a moderate increase in normal-looking MZ cells, judged to be prelymphomatous, and 2) MZL in three variants: i) distinct enlargement of MZ by normal-looking cells (MZL), ii) distinct enlargement of MZ by basophilic centroblast-like cells (MZL+), and iii) extensive splenic involvement by centroblast-like cells (MZL++). The rate of mitosis and apoptosis increases with lymphoma grade. In most cases, emergence of a dominant IgH clonal pattern in paired splenic biopsy and necropsy samples was correlated with progression. MZLs were transplantable and homed to the spleen. MZL may constitute a commonly occurring lymphoma type unrecognized, in part, because of the centroblastic morphology of high-grade MZL and possible overgrowth of lower-grade MZL by more aggressive follicular lymphomas.
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PMID:Splenic marginal zone lymphomas of mice. 1007 58

Mutations of the p53 tumour suppressor gene are infrequent at presentation of both acute myeloblastic leukaemia (AML) and acute lymphoblastic leukaemia (ALL), being found in between 5-10% of AML and 2-3% of ALL. Here we have studied the frequency of detection of p53 mutations at relapse of both AML and B-precursor ALL. In those patients with detectable mutations at relapse we investigated whether the mutation was detectable at presentation and was thus an early initiating event or whether it had arisen as a late event associated with relapse. Bone marrow samples from 55 adults and children with relapsed AML (n = 41) or ALL (n = 14) were analysed for p53 gene alterations by direct sequencing of exons 5-9. For samples where a p53 mutation was found at relapse, analysis of presentation samples was carried out by direct sequencing of the exon involved, or by allele-specific polymerase chain reaction (PCR) if the mutation could not be detected using direct sequencing. A p53 mutated gene was found at relapse in seven out of 55 cases. The frequency was higher in relapsed ALL (four out of 14 cases; 28.6%) compared to AML (three out of 41 cases; 7.3%). In five out of the seven cases presentation samples were available to study for the presence of the mutation. In two out of two AML patients the p53 mutation was detectable in the presentation sample by direct sequencing. In three ALL patients analysis of presentation material by direct sequencing showed a small mutant peak in one case, the other two being negative despite the sample analysed containing > 90% blast cells. However in both of these patients, the presence of p53 mutation was confirmed in the presentation sample using allele-specific PCR. In one of these patients the emergence of a subclone at relapse was confirmed by clonality analysis using IgH fingerprinting. Our results confirm that in ALL p53 mutations are present in a proportion of patients at relapse. Furthermore cells carrying the mutation are detectable at presentation in a minor clone suggesting that p53 mutations in ALL may be a mechanism contributing to disease relapse.
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PMID:Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia. 1009 50

Assembly of immunoglobulin (Ig) heavy (H) variable (V), diversity (D) and joining (J) gene segments constitutes an important determinant of commitment to the B cell lineage. The randomly selected D gene segment of a given VDJ complex can potentially be found in all three possible reading frames (RFs). In the present study, we examined the distribution of D gene RF in 'immature' and 'mature' B cell lymphoproliferative disorders (BCLD). We analyzed the clonotypic VDJ junctional sequences of our previously reported cases of follicular lymphoma (FL), as well as bcl-2/IgH junctions with recognized D elements. A marked under-representation of RF1 was observed, with almost equal usage of RF2 and RF3. A literature search for VDJ published sequences in various BCLD identified a similar pattern of D gene RF usage in multiple myeloma (MM), with marked predilection for RFs 2 and 3. In B cell chronic lymphocytic leukemia (B-CLL), the pattern of D-RF was 25% for RF1, 46% for RF2 and 29% for RF3, while in B cell precursor acute lymphoblastic leukemia (precursor-B-ALL) all three RFs were used with similar frequencies. The marked under-representation of RF1 in FL and MM clonogenic rearranged D genes suggests selection on the basis of antigenic properties, possibly due to constraints in forming a flexible loop within CDR3. In contrast, the more even distribution of D-RF usage in B-CLL and precursor-B-ALL suggests that, for these disorders, transformation of a immature type B cell repertoire has occurred.
Leukemia 1999 Apr
PMID:Selection of immunoglobulin diversity gene reading frames in B cell lymphoproliferative disorders. 1021 68

Children with acute lymphoblastic leukemia (ALL) with > or = 0.01% leukemic cells in the bone marrow after remission induction are at a greater risk of relapse. The most promising methods of detecting minimal residual disease (MRD) are flow cytometric identification of leukemia-associated immunophenotypes and polymerase chain reaction (PCR) amplification of antigen-receptor genes. However, neither assay can be applied to all patients. Moreover, both assays carry the risk of false-negative findings due to clonal evolution. The simultaneous use of both assays might resolve these problems, but the correlation between the methods is unknown. We studied serial dilutions of normal and leukemic cells by flow cytometry and PCR amplification of IgH genes and found the two methods highly sensitive (one leukemic cell among 10(4) or more normal cells), accurate (r2 was 0.999 for flow cytometry and 0.960 for PCR by regression analysis) and concordant (r2 = 0.962). We then examined 62 bone marrow samples collected from children with ALL in clinical remission. In 12 samples, both techniques detected MRD levels > or = 1 in 10(4). The percentages of leukemic cells measured by the two methods correlated well (r2 = 0.978). Of the remaining 50 samples, 48 had MRD levels < 1 in 10(4). In only two samples results were discordant: 2 in 10(4) and 5 in 10(4) leukemic cells by PCR but < 1 in 10(4) by flow cytometry. We conclude that immunologic and molecular techniques can be used in tandem for universal monitoring of MRD in childhood ALL.
Leukemia 1999 Aug
PMID:Tandem application of flow cytometry and polymerase chain reaction for comprehensive detection of minimal residual disease in childhood acute lymphoblastic leukemia. 1045 Jul 50

Immunoglobulin kappa (Igkappa) gene recombinations can be used - similarly to IgH rearrangements - as clonal markers in B-lineage leukaemias. Based on the extensive junctional diversity, these rearrangements represent valuable targets for the analysis of minimal residual disease (MRD). In order to provide a simple method for the rapid detection of leukaemia clone-specific kappa deleting element (Kde) mediated rearrangements, we developed a multiplex PCR reaction that is able to amplify the five most frequent rearrangements in one tube. Position of the amplimers were chosen to enable identification of the involved segments according to the size of the PCR product. This method was tested on 101 B-lineage leukaemias (71 childhood B-cell precursor acute lymphoblastic leukaemias (BCP ALL) and 30 chronic lymphocytic leukaemias (CLL)). 39 and 22 Kde rearrangements could be readily detected in 30 (44%) BCP ALL and 22 (56%) CLL, respectively. 36% of the Kde rearrangements in BCP ALL and 45% in CLL were intron recombination signal sequence (RSS)-Kde rearrangements. The other Kde rearrangements involved the Vkappa families: VkappaI in 36% and 50%, VkappaII in 32% and 16.7%, VkappaIII in 24% and 25%, and VkappaIV in 8% and 8.3% in BCP ALL and CLL, respectively. The sensitivity of the multiplex system was 10-2-10-3. We compared this multiplex PCR assay with multiple single PCR reactions using different sets of primer combinations. Thereby the number and types of rearrangements were confirmed in all cases. Clonality of rearrangements was proven by sequence analysis. Our data show that by this method clonal Kde rearrangements were rapidly detected and precisely identified.
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PMID:Multiplex PCR reaction for the detection and identification of immunoglobulin kappa deleting element rearrangements in B-lineage leukaemias. 1046 Jun 10

A sensitive, safe and cheap method to detect minimal residual disease (MRD) is here presented. The PCR-GS technique includes: (a) a fluorescent PCR for the IgH region with CDR3/JH consensus primers; (b) the electrophoresis on an automatic sequencer (ABI PRISM 310); (c) the analysis of results by the GeneScan program. A total of 72 samples were analysed: 34/49 B-cell Non-Hodgkin's Lymphoma (NHL) (69%), six out of seven Multiple Myeloma (MM) (86%), 1/2 Hodgkin's Disease (HD) and 4/4 Acute Lymphoblastic Leukaemia (ALL) were found to be positive, showing a monoclonal IgH rearrangement. The major bias of the PCR-GS method are the 21% of false negatives, but 13/15 negative patients carried t(14;18); consequently, the association of the evaluation by PCR assays of the IgH and BCL2/JH rearrangement allowed to detect a molecular marker of B-neoplasia in more than 94% of tested samples.
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PMID:An advantageous method to evaluate IgH rearrangement and its role in minimal residual disease detection. 1057 38

The significance of random cytogenetic abnormalities detected in pediatric acute lymphoblastic leukemia (ALL) during remission is unknown. We studied 10 of 72 consecutive ALL patients who developed cytogenetic abnormalities during clinical remission to determine their effect on remission status. The cytogenetic abnormalities occurred at a median of 14.5 months (range 5-72) from the initial diagnosis. Five abnormalities were designated as clonal (monosomy 21 in three metaphases and 64 approximately 69,XXY in three metaphases from one patient at different times, and del(20)(q12q13) in three metaphases, add(13)(q34) in two metaphases, and ?del(19)(p11) in two metaphases from three different patients). Seven abnormalities were previously described: del(5)(q12), del(5)(q33), -7, del(11)(q23), +12, and +13 each in one metaphase, and del(20)(q12q13) in three metaphases). The remaining cytogenetic abnormalities were nonclonal and random. Flow cytometry and analysis of IgH and TcR gene rearrangements showed that all evaluable patients were in immunophenotypic and molecular remission, respectively. Eight patients remain in clinical and molecular remission a median of 9 months (range 7-18) after detecting the cytogenetic abnormality, and the leukemia in two patients has relapsed. During remission, cytogenetic abnormalities may not be a harbinger of leukemia relapse in pediatric ALL; therefore, a wait-and-see approach is prudent.
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PMID:Cytogenetic abnormalities during clinical, immunophenotypic, and molecular remission in pediatric acute lymphoblastic leukemia. 1073 83

A number of prospective studies have indicated the clinical utility of measuring minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia (ALL) and have highlighted the need for improved methodology for quantification of residual disease. We describe a novel real-time polymerase chain reaction (PCR) strategy for MRD analysis based on the exonuclease activity of Taq polymerase to cleave a fluorescently labelled probe. Using a consensus probe designed to the framework 2 region of the IgH gene, together with leukaemia-specific primers, the utility of this technique for simultaneous detection and quantification of MRD was demonstrated in samples from six ALL patients. This technique provides a rapid quantitative assay for determining MRD levels which lends itself to the routine monitoring of minimal residual leukaemia.
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PMID:Simultaneous detection and quantification of minimal residual disease in childhood acute lymphoblastic leukaemia using real-time polymerase chain reaction. 1084 37


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