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B-cell Chronic Lymphocytic Leukaemia (b-cell + chronic_lymphocytic_leukaemia)
Selected AbstractsSubclinical chronic lymphocytic leukaemia associated with a 13q deletion presenting initially in the skin: apropos of a caseJOURNAL OF CUTANEOUS PATHOLOGY, Issue 3 2006Abha Khandelwal Introduction:, B-cell chronic lymphocytic leukaemia (B-CLL) represents a low-grade B-cell lymphoproliferative disease that is the most common leukaemia in adults. The neoplastic cell is an autoreactive CD5 CD23 B lymphocyte. B-CLL may involve the skin, typically in the context of known disease. We present a case of subclinical B-CLL presenting initially in the skin. Case Report:, A 73-year-old male developed a lesion on his right cheek in April 2003 compatible with basal cell carcinoma. The re-excision specimen contained a well-differentiated atypical lymphocytic infiltrate consistent with B-CLL along with residual carcinoma. Subsequent laboratory studies revealed peripheral blood lymphocytosis with smudge cells. A diagnosis was made of Rai stage 0 CLL. Chromosomal studies on peripheral blood showed a deletion at 13q14.3. Excision of a second primary skin carcinoma revealed a squamous cell carcinoma in association with B-CLL that was identical to his previously diagnosed skin involvement. Conclusion:, This case identifies a cutaneous presentation of subclinical B-CLL. There are two prior reports describing B-CLL presenting initially in the skin. In one case, the infiltrates were incidental on a re-excision specimen. The second report suggests 16% of B-CLL patients have cutaneous manifestations as the first sign of disease. [source] Postzoster cutaneous pseudolymphoma in a patient with B-cell chronic lymphocytic leukaemiaJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 8 2007E Moreira [source] Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2007Amy J. Johnson Summary Treatment options for chronic lymphocytic leukaemia (CLL) are limited and eventually fail because of the development of toxicities or drug resistance. Thus, identification of new therapeutic strategies and targets is a high priority. The semisynthetic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90 (Hsp90) binding to client proteins, thereby leading to their degradation. We demonstrate that at biologically active and clinically attainable levels (1 ,mol/l), 17-AAG treatment of CLL B cells in vitro causes modest apoptosis as well as decreased AKT protein levels. Given the potential activation of AKT following antibody therapy in CLL, we evaluated the combination of 17-AAG and rituximab. These agents produced synergistic cytotoxicity of CLL cells in vitro. However, rituximab-mediated antibody-dependent cellular cytotoxicity was modestly reduced with 17-AAG, and complement-dependent cytotoxicity was not altered. We conclude that the combination of Hsp90 inhibitors with therapeutic antibodies, such as rituximab may represent a novel strategy to enhance therapeutic response in CLL. Furthermore, our data indicates that AKT and Hsp70 protein levels are relevant pharmacodynamic endpoints to monitor the in vivo effect of 17-AAG therapy. [source] Mutagenicity of non-homologous end joining DNA repair in a resistant subset of human chronic lymphocytic leukaemia B cellsBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006Ludovic Deriano Summary Non-homologous end joining (NHEJ) is an important determinant of genomic stability in mammalian cells. This DNA repair pathway is upregulated in a subset of B-cell chronic lymphocytic leukaemia (B-CLL) cells resistant to DNA damage-induced apoptosis. Using an in vitro assay for double-strand breaks (DSB) end ligation, we studied the fidelity of DSB repair in B-CLL cells which were resistant or sensitive to in vitro DSB-induced apoptosis with concomitant patients' resistance or sensitivity to chemotherapy, respectively. The fidelity of DNA repair was determined by DNA sequencing of polymerase chain reaction products cloned in pGEM-T vector. Sequence analysis of DNA end junctions showed that the frequency of accurate ligation was higher in sensitive B-CLL cells and control cell lines, than in resistant cells where end joining was associated with extended deletions. Upregulated and error-prone NHEJ in resistant cells could be a quite possible mechanism underlying both genomic instability and poor clinical outcome. [source] IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2006Davide Bagnara Summary Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one VLJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s). [source] Expression of C-IAP1, C-IAP2 and SURVIVIN discriminates different types of lymphoid malignanciesBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2005Aniek O. de Graaf Summary (De-)regulation of apoptosis plays an important role in normal and malignant lymphopoiesis. Apoptosis-regulating genes of the BCL-2 family and the recently identified inhibitors of apoptosis (IAP) family have been implicated in different types of non-Hodgkin lymphoma (NHL). To investigate whether expression of specific apoptosis-regulating genes correlated with different types of lymphoid malignancies, we measured the expression of five BCL-2 family genes, four IAP family genes and SMAC by real-time quantitative polymerase chain reaction in patient samples. In total, 137 samples from B- and T-cell acute lymphoblastic leukaemia (ALL), B-cell chronic lymphocytic leukaemia (CLL), six different NHL types and three control tissue types were analysed. The data were further analysed using cluster and discriminant analysis. Three specific expression patterns were identified for CLL, ALL and NHL respectively. CLL samples, as well as B-ALL and follicular lymphoma samples showed high similarity in the expression of these apoptosis-regulating genes and could be distinguished from each other and other diseases and controls. Discriminant analysis identified three members of the IAP family, C-IAP1, C-IAP2 and SURVIVIN, as the most informative genes to discriminate between these lymphoid malignancies. [source] A prognostic model for survival in chronic lymphocytic leukaemia based on p53 expressionBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2003Francis J. Giles Summary. As the abnormal expression of p53 protein is prognostically significant in some human cancers, its significance in patients with B-cell chronic lymphocytic leukaemia (CLL) was assessed. Two investigators evaluated the percentage of bone marrow mononuclear cells that stained for p53, using biopsies stained with anti-p53 monoclonal antibody (DO-7), and graded the degree of staining (0, +, ++, +++). Samples from a cohort of 90 patients with CLL were studied (median age 60 years, range 30,89 years; 57 patients were (63%) previously untreated, 22 patients (24%) had received one or two prior regimens, 11 patients had received (12%) three to seven regimens. The overall percentage of cells positive for p53 staining was a median of 43 (range 1,88). No investigator effect was detected either in overall percentage cells rated p53 positive or on the degree of staining (Pearson's correlation coefficient 0·980, P -value <,0·001). A Cox proportional hazards model showed that the percentage of ++ and +++ p53-positive cells correlated with various prognostic factors in CLL (P < 0·0001). A multivariate model incorporating prior therapy, Rai stage, beta2 microglobulin (,2M) and p53 expression showed that only the percentage of p53-positive cells and ,2M were predictive of survival, and enabled the development of a highly predictive model of survival based on these two parameters. [source] CD40L stimulation enhances the ability of conventional metaphase cytogenetics to detect chromosome aberrations in B-cell chronic lymphocytic leukaemia cellsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2002Raymund Buhmann Summary. Conventional metaphase cytogenetics underestimates the frequency of specific chromosome aberrations in B-cell chronic lymphocytic leukaemia (B-CLL) as a result of the very low proliferative activity of these cells in vitro. New molecular approaches, such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH), may circumvent this problem, at least in part, but these techniques are either strongly dependent on the knowledge of candidate regions or detect only unbalanced aberrations. In the present study, we analysed 27 B-CLL peripheral blood samples by metaphase cytogenetics after CD40 ligand (CD40L)-induced cell cycle stimulation. In comparison with the simultaneous use of B-cell mitogens such as 12-O-tetradecanoylphorbol-13-acetate (TPA), lipopolysaccharide (LPS) and pokeweed mitogen (PWM), CD40L stimulation of B-CLL cells induced a threefold increase in metaphases amenable to analysis by conventional cytogenetics. The analysis of these metaphases confirmed all genetic abnormalities detected by FISH. Moreover, CD40L-enhanced cytogenetics revealed complex karyotypic aberrations in 11 out of 27 patients (41%). In one case, a balanced translocation t(11;16)(p15;p13.1), so far unreported in B-CLL, was detected. Taken together, the results of our study show the potential of CD40L-enhanced metaphase cytogenetics to detect more and new chromosome aberrations in B-CLL. [source] Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug aloneBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2001N. Di Gaetano We have shown previously that the anti-CD20 chimaeric monoclonal antibody rituximab exerts its effects on neoplastic B-lymphoma cell lines in part via complement-dependent cytotoxicity. In addition, membrane expression levels of complement inhibitory proteins CD55 and CD59 play a role in determining susceptibility to lysis. We have identified one t(14;18)-positive human B-cell non Hodgkin's lymphoma cell line (Karpas 422) that is resistant to rituximab and complement and used it for subsequent studies on the possible interaction between this novel therapeutic agent and established antineoplastic drugs. We have exposed Karpas to several chemotherapeutic agents (doxorubicin, idarubicin, cisplatin, taxol) for different time periods and subsequently exposed the cells to rituximab and human complement. The combination of these drugs with rituximab induced an additive cytotoxic effect. In contrast, exposure to fludarabine (1 µg/ml for 48,72 h) showed a synergistic effect, with cell lysis increasing from 10% to 20% using fludarabine or rituximab and complement alone to about 70% with both cytotoxic agents. Analysis of the mechanism for this synergistic effect showed that fludarabine downmodulates the membrane expression of CD55 (from 96% to 55% positive cells) without significantly altering CD20 levels. Northern analysis demonstrated that fludarabine induced a general downmodulation of steady state mRNA levels with no change in transcription rate detected in run-off assays. The study of the effect of fludarabine and rituximab in six freshly isolated B-cell chronic lymphocytic leukaemia (B-CLL) samples showed that, in most cases, fludarabine has an additive cytotoxic activity with rituximab and complement. This report gives a rational support for clinical studies with combinations of drugs, including monoclonal antibodies and fludarabine. [source] Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2000Mohammad Reza Rezvany We have previously shown that autologous T cells recognize leukaemic cells from patients with chronic lymphocytic leukaemia (B-CLL) in an MHC class I- and/or II-restricted manner. A candidate recognition structure might be the tumour cell-derived Ig VH complementarity-determining region (CDR)3. Three patients with B-CLL were analysed for the presence of autologous T cells recognizing the tumour-specific VH-CDR3 region. The VH region was shown to be mutated in all three patients. In two patients, a VH-CDR3-specific T-cell response was detected by proliferation assay, as well as by ,-interferon (IFN) production. The responses could be inhibited by monoclonal antibodies against MHC class II, but not MHC class I. In the third patient, a VH-CDR3 proliferative response was detected, which could be inhibited by an anti-MHC class I monoclonal antibody, but not by anti-MHC class II antibodies. No ,-IFN response could be detected in this patient. In no patient was an interleukin (IL)-4 response noted. Thus, in patients with B-CLL, naturally occurring T cells recognizing the tumour-unique VH-CDR3 region are present. [source] | ||||||||||