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Query: UNIPROT:P06889 (Mol)
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We describe here computer-assisted homology models of the combining site structure of three polyreactive immunoglobulins. Template-based models of Fv (VL-VH) fragments were derived for the surface IgM expressed by the malignant CD5 positive B cells from three patients with chronic lymphocytic leukaemia (CLL). The conserved framework regions were constructed using crystal coordinates taken from highly homologous human variable domain structures (Pot and Hil). Complementarity determining regions (CDRs) were predicted by grafting loops, taken from known immunoglobulin structures, onto the Fv framework models. The CDR templates were chosen, where possible, to be of the same length and of high residue identity or similarity. LCDR1, 2 and 3 as well as HCDR1 and 2 for the Fv were constructed using this strategy. For HCDR3 prediction, a database containing the Cartesian coordinates of 30 of these loops was complied from unliganded antibody X-ray crystallographic structures and an HCDR3 of the same length as that of the B CLL Fv was selected as a template. In one case (Yar), the resulting HCDR3 model gave unfavourable interactions when incorporated into the Fv model. This HCDR3 was therefore modelled using an alternative strategy of construction of the loop stems, using a previously described HCDR3 conformation (Pot), followed by chain closure with a beta-turn. The template models were subjected to positional refinement using energy minimisation and molecular dynamics simulations (X-PLOR). An electrostatic surface description (GRASP) did not reveal a common structural feature within the binding sites of the three polyreactive Fv. Thus, polyreactive immunoglobulins may recognise similar and multiple antigens through a diverse array of binding site structures.
J Comput Aided Mol Des 1997 Sep
PMID:Diverse binding site structures revealed in homology models of polyreactive immunoglobulins. 938 49

Nonrandom use of immunoglobulin variable (V) gene segments is a feature of some B-cell neoplasms, possibly as a consequence of antigen selection. In Hodgkin's disease, the primary tissues, cell lines, and even single Reed-Sternberg cells can carry immunoglobulin gene rearrangements. Here, we examined the immunoglobulin heavy-chain genes of a well-characterized Hodgkin's-derived cell line, L428, and found a hypermutated VH32 gene involving a conventional V(N)D(N)J4-C gamma 4 rearrangement. VH32 is one of two rearranging members of the VH5 family that is also rearranged preferentially in some B-cell neoplasms and familial CLL. Unexpectedly, the closest known rearranged sequence match for the rearranged VH gene of L428 was found in the single Reed-Sternberg cells of lymphocyte-predominance Hodgkin's disease, and is a mutated VH251, the only other rearranging member of the VH5 family. Assuming random usage of the human VH pool, the chance of coincident VH5 family gene rearrangement in the two cases of Hodgkin's disease is only about 10(-3). Biased use of VH genes suggests a B-cell target that is either selected by antigen or vulnerable to transformation at an early antigen-independent, developmental stage. These findings raise the question whether similar processes operate in Hodgkin's disease.
Hematopathol Mol Hematol
PMID:Rearrangement, hypermutation, and possible preferential use of a VH5 gene, VH32, in a Hodgkin's cell line. 943 77

The diagnosis of marrow involvement in non-Hodgkin's lymphoma (NHL) relies on morphology with support from immunophenotyping by flow cytometry (FCM). We assessed the relative sensitivity of morphology, FCM, and consensus primer polymerase chain reaction (PCR) of antigen receptor genes in the detection of marrow involvement. In 78 of 100 (78%) cases, there was concordance between FCM and PCR. FCM detected more cases of clonality in B-cell neoplasia. There were 40 cases with objective evidence of involvement by B-cell neoplasia. In this group, FCM had a sensitivity of 97.5% (39 of 40); PCR had a sensitivity of 67.5% (27 of 40). In contrast, PCR had a sensitivity of 71.4%, and FCM a sensitivity of 28.6%, in T-cell neoplasia. In all 12 cases with involvement detected by biopsy, there was objective evidence of clonality. However, clonality was detected in four of seven patients with chronic lymphocytic leukemia and in five of eight patients with T-cell neoplasia in the absence of morphologically detectable disease. Clonality was identified in only one of seven patients with B-cell lymphoma in which the biopsy was interpreted as "suspicious but not diagnostic of involvement." We conclude that morphology remains of central importance in the evaluation of marrow involvement in NHL. We show that FCM and PCR identify involvement in the absence of morphologically apparent disease. In B-cell neoplasms, FCM remains the method of choice for the detection of clonality. PCR for T-cell receptor gene rearrangements may be an important adjunct to the diagnosis of marrow involvement in patients with T-cell neoplasms.
Diagn Mol Pathol 1998 Apr
PMID:Morphologic, immunophenotypic, and molecular evaluation of bone marrow involvement in non-Hodgkin's lymphoma. 978 7

Detection of clonal tumor cells in leukemias and lymphomas by PCR in minimal residual disease (MRD) has been shown to be a valuable parameter for identifying patients who may require further treatment. Here we introduce the studies underway in our own and other institutions addressing the value of PCR technology in detecting residual CLL cells either in the autologous stem cell product or after induction of MRD in patients after autologous or allogeneic stem cell transplant. The PCR technology used for these questions and the results are discussed.
J Mol Med (Berl) 1999 Feb
PMID:Minimal residual disease detection after myeloablative chemotherapy in chronic lymphatic leukemia. 1002 79

Chronic lymphocytic leukemia is a malignant disease characterized by clonal expansion of relatively mature B-lymphocytes with a high percentage of cells arrested in the nonproliferative G0/G1 cell cycle phase. Possibly reflecting the clinical heterogeneity observed in patients, various signaling pathways may become affected during the initiation and course of this disease. This review discusses frequent alterations concerning proliferative, differentiation-inducing, and apoptotic pathways elucidated in the recent years that have improved our understanding of this disease.
J Mol Med (Berl) 1999 Feb
PMID:Molecular pathogenesis of chronic lymphocytic leukemia: factors and signaling pathways regulating cell growth and survival. 1002 81

While t(1;19) and t(8;14) have been reported singly in pre-B-ALL and Burkitt's lymphoma, respectively, the occurrence of both translocations simultaneously in the same patient is rare. Indeed, a review of the English literature from 1966 to 1999 revealed no case reports with these findings. We report here an 88-year-old patient who was clinically diagnosed to have chronic lymphocytic leukemia and who carried both translocations in her peripheral blood cells. The patient refused to give consent for a bone marrow sample, the preferred tissue for study. The patient's clinical findings are discussed, although the relationship between the clinical information and cytogenetic findings, if any, is not known. Study of additional cases identical to ours will be helpful in determining the correlation, if any, between the patient's phenotype and the occurrence of the two translocations.
Exp Mol Pathol 1999 Aug
PMID:Occurrence of both t(1;19) and t(8;14) in a patient with chronic lymphocytic leukemia. 1048 42

WSU-CLL cells, a fludarabine resistant B-cell chronic lymphocytic leukemia cell line, has been shown to exhibit enhanced sensitivity to 2-chlorodeoxyadenosine (2-CdA) following 48-72 h exposure to bryostatin 1. For 2-CdA to manifest its chemotherapeutic activity, it must first enter the cell through one of several specific nucleoside transporter systems. We present data to show that bryostatin 1-induced enhanced influx of 2-CdA is in part the result of bryostatin 1-induced modulation of nucleoside transporters in WSU-CLL cells. The bi-directional equilibrative NBMPR sensitive transporters in WSU-CLL cells were significantly down-regulated 90 min post-exposure to 1-200 nM bryostatin 1. This down-regulation was evident up to 144 h. In contrast, WSU-CLL cells exhibited a transient increase in Na+-dependent concentrative 2-CdA influx from 48 to 96 h after bryostatin 1 exposure which was evident for a longer duration than that accounted for by the increase in deocycytidine kinase activity. These data may, in part, explain the enhanced efficacy of 2-CdA seen in WSU-CLL cells following 48-72 h exposure to bryostatin 1. It may raise questions as to the importance of the bi-directional transporters in determining the resistance or sensitivity of CLL cells to 2-CdA or other nucleoside analogues.
Int J Mol Med 2000 Apr
PMID:Bryostatin 1-induced modulation of nucleoside transporters and 2-chlorodeoxyadenosine influx in WSU-CLL cells. 1071 48

The cytosolic 3'-to-5' exonuclease from chronic lymphocytic leukemia cells was highly purified, and its ability to remove beta-D- and beta-L-nucleotide analogs from the 3'-end of DNA was determined. The relative rate of excision of beta-D-ddCMP, beta-L-ddCMP, beta-L-FddCMP, beta-L-SddCMP, beta-L-Fd4CMP, and beta-L-OddCMP from the 3'-end of a single-stranded oligonucleotide primer or a primer annealed with complementary DNA and/or RNA templates was assessed. The rate of excision of beta-D-nucleotides from the 3'-end of DNA was higher than that of beta-L-nucleotides, which could be partly attributable to the affinity of the enzyme to beta-D-nucleotide-terminated DNA being 5-fold higher compared with that of beta-L-nucleotide-terminated DNA. The rate of removal of beta-L-Fd4CMP and beta-L-OddCMP from the 3'-end of DNA was at least 8 to 10 times lower compared with that of beta-L-SddCMP. HIV reverse transcriptase could elongate DNA primers after the removal of chain terminators by the cytosolic exonuclease. Concentrations of nucleoside 5'-monophosphate analogs that inhibit the cytosolic exonuclease by 50% were estimated. Among the nucleoside 5'-monophosphate analogs examined, beta-L-Fd4CMP appeared to be the most effective inhibitor of the cytosolic exonuclease, with an ID(50) value of 38 microM.
Mol Pharmacol 2000 May
PMID:Excision of beta-D- and beta-L-nucleotide analogs from DNA by the human cytosolic 3'-to-5' exonuclease. 1077 91

Immunophenotypic analysis is critical in categorizing small B-cell neoplasms; however, many recommended antibody panels have required fresh or frozen tissue. Many paraffin-reactive antibodies are now available but have been studied mostly in isolation. Therefore, the utility of a panel of paraffin-reactive antibodies in differentiating small B-cell neoplasms was investigated. Paraffin-embedded sections of small lymphocytic lymphoma/B-chronic lymphocytic leukemia (SLL/B-CLL; 12), mantle cell (MCL; 15), follicular (FL; 11), and marginal zone B-cell (MZL; eight) lymphomas were stained with CD20/L26, CD3, CD43/DF-T1 or Leu22, CD5/4C7, CD23/BU38, cyclin D1/H295, and CD10/56C6 antibodies. For select antibodies, results were compared to flow cytometric data (FC). Formalin and B5 fixation were also compared. Seven of 11 SLL/B-CLL were CD43+ CD5+ CD23+ cyclin D1- CD10-; seven of 11 MCL were CD43+ CD5+ CD23- cyclin D1+ CD10-; nine of 10 FL were CD43- CD5- CD23- cyclin D1- CD10+; and five of six MZL were CD43+ CD5- CD23- cyclin D1- CD10-. CD5, CD23, and CD10 stains showed sensitivities of 81, 88, and 100%, respectively, compared to FC. With B5 fixation, cyclin D1 was more often negative and CD5 more often equivocal. A panel of paraffin-reactive antibodies aids in classification of small B-cell neoplasms, although a small number of cases have indeterminate phenotypes and MZL have no defining features. CD5 separates most SLL/B-CLL and MCL from FL and MZL. CD23 separates SLL/B-CLL from most MCL, but cyclin D1 is most important for identifying MCL. CD10 positivity distinguishes most FL from other small B-cell lymphoid neoplasms.
Appl Immunohistochem Mol Morphol 2000 Mar
PMID:Classification of small B-cell lymphoid neoplasms using a paraffin section immunohistochemical panel. 1093 42

Chronic lymphocytic leukemia (CLL) is characterized by the gradual accumulation of immature B-lymphocytes. CLL B-lymphocytes mature to a plasmacytoid phenotype when treated in vitro with phorbol esters. CLL B-cell apparent maturation is associated with altered expression of specific plasma membrane and mitochondrial proteins including heightened expression of a 30-kDa heat shock protein 60 (hsp60) analog. During our efforts to further characterize this hsp60 analog by mass spectrometry, we detected the mitochondrial protein prohibitin in phorbol-ester-matured CLL B-lymphocytes. Prohibitin modulates cell proliferation and inhibits cell cycle traverse in several systems, although few data are available for lymphocytes. A twofold increase in prohibitin concentration was observed in phorbol-ester-matured compared to resting CLL B-cells as determined by quantitative Western immunoblot analysis. A similar increase in prohibitin was observed in phorbol-ester-treated normal human B-lymphocyte populations. An antisense oligonucleotide complementary to the 5' coding region of the prohibitin gene blunted the increase in prohibitin protein in phorbol-ester-treated CLL B-cells by 42%. These data suggest that increased prohibitin expression is associated with and may facilitate B-cell maturation.
Blood Cells Mol Dis
PMID:Prohibitin expression is increased in phorbol ester-treated chronic leukemic B-lymphocytes. 1116 43


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