National Cancer Institute®
Last Modified: February 1, 2002
UI - 11521806
AU - Novak U; Grob TJ; Baskaynak G; Peters UR; Aebi S; Zwahlen D; Tschan MP;
TI - Kreuzer KA; Leibundgut EO; Cajot JF; Tobler A; Fey MF Overexpression of the p73 gene is a novel finding in high-risk B-cell chronic lymphocytic leukemia.
SO - Ann Oncol 2001 Jul;12(7):981-6
AD - University and Inselspital, Department of Clinical Research, Medical Oncology/Haematology, Berne, Switzerland.
The p73 protein shares structural and functional similarities with the tumour-suppressor p53, but its role in neoplastic transformation is unknown. Alternative splicing leads to the expression of at least nine p73 C-terminal mRNA splice variants (alpha, beta, gamma, delta, epsilon, zeta, eta, eta1, theta). In this survey, we analyse the expression of p73 by real-time quantitative RT-PCR, its known C-terminal variants with an RT-PCR-Southern technique and by Western blot in samples of 51 patients with B-CLL, normal B lymphocytes from eight individuals, and five haematopoetic cell lines. p73alpha protein expression positively correlated with higher risk B-CLL stages (P = 0.046). Total p73 mRNA expression was higher (P = 0.01) and p73alpha protein more frequently detected (P = 0.008) in B-CLL compared with normal CD19+-B-lymphocytes. p73 C-terminal mRNA variants were expressed both in B-CLL and in normal B-lymphocytes, but their expression was biased since the gamma (P = 0.041), the theta (P < 0.001), and the eta variant (P = 0.033) prevailed in normal B-lymphocytes. In summary, we conclude that the accumulation of p73, the expression pattern of particular p73 variants and its link to progression may play a distinct role in the molecular pathology B-CLL.
UI - 11797117
AU - Sugimoto T; Imoto S; Matsuo Y; Kojima K; Yasukawa M; Murayama T; Kohfuku
TI - J; Mizuno I; Yakushijin K; Sada A; Nishimura R; Koizumi T T-cell receptor gammadelta T-cell leukemia with the morphology of T-cell prolymphocytic leukemia and a postthymic immunophenotype.
SO - Ann Hematol 2001 Dec;80(12):749-51
AD - Clinical Research Institute, Hyogo Medical Center for Adults, Hyogo, Japan.
T-cell prolymphocytic leukemia (T-PLL) is a postthymic T-cell neoplasm with a characteristic morphology and heterogeneous immunophenotype. Most cases of T-PLL express membrane T-cell receptors (TCRs) of the alphabeta phenotype. We experienced a 30-year-old man suffering from TCRgammadelta T-cell leukemia with morphology compatible to T-PLL with a postthymic phenotype. He was admitted with skin eruption and pancytopenia. Peripheral blood and bone marrow were occupied with medium-sized lymphocytes, which had moderately condensed chromatin with a single nucleolus and sparse, nongranular basophilic cytoplasm. The immunophenotype was CD1a-, CD2-, CD3+, CD4-, CD5+, CD7+, CD8-, and terminal deoxynucleotidyl transferase negative. Hepatosplenomegaly was absent. He was diagnosed as having T-PLL and was treated with combination chemotherapy. Six months later the leukemic cell became chemoresistant. Although the patient showed transient improvement in response to pentostatin, he died 13 months after the diagnosis. To our knowledge, this is the first case of T-PLL with a TCRgammadelta phenotype.
UI - 11778765
AU - Pangalis GA; Dimopoulou MN; Angelopoulou MK; Tsekouras C;
TI - Vassilakopoulos TP; Vaiopoulos G; Siakantaris MP Campath-1H (anti-CD52) monoclonal antibody therapy in lymphoproliferative disorders.
SO - Med Oncol 2001;18(2):99-107
AD - 1st Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, Greece. email@example.com
Campath-1H is a humanized monoclonal antibody targeted against the CDw52 membrane antigen of lymphocytes, which causes complement and antibody-dependent cell-mediated cytotoxicity. Campath-1H has been used in B-chronic lymphocytic leukemia (B-CLL), T-prolymphocytic leukemia (T-PLL), and low-grade non-Hodgkin's lymphoma (LGNHL). Campath-1H is administered intravenously thrice weekly for up to 12 wk, at an initial dose of 3 mg, escalated to 10 and 30 mg. The responses (complete [CR] and partial [PR]) obtained in untreated B-CLL patients are of the order of 90%. In previously treated B-CLL patients, responses are of the order of approximately 40%, with 2-4% CRs. Responses are more prominent in the blood and bone marrow compared to the lymph nodes. The median duration of response is 9-12 mo. Because of the antibody's higher activity on circulating lymphocytes, it has been used for in vivo purging of residual disease in B-CLL, followed by autologous stem-cell transplantation. In heavily pretreated advanced stage LGNHL, response is achieved only in 14% of cases with B-phenotype; a 50% response rate is noted in mycosis fungoides. In T-PLL, the CR rate is approximately 60%. Promising results have been reported in a small number of patients with refractory autoimmune thrombocytopenia of lymphoproliferative disorders. The main complications of Campath-1H treatment are caused by tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 release, usually during the first intravenous infusion, and include fever, rigor, nausea, vomiting, and hypotension responsive to steroids. These side effects are usually less severe with subsequent infusions and can be prevented by paracetamol and antihistamines. Immunosupression resulting from normal B- and T-lymphocyte depletion is frequent, resulting in an increased risk for opportunistic infections. More clinical trials in a larger number of patients are necessary to determine the exact role and indications of Campath-1H in lymphoproliferative disorders.
UI - 11771308
AU - Tiazhelova TV; Ivanov DV; Makeeva NV; Kapanadze BI; Nikitin EA; Semov
TI - AB; Sangfeldt O; Grander D; Vorob'ev AI; Einhorn S; Iankovskii NK; Baranova AV [Transcription map of the 13q14 region, frequently deleted in B-cell chronic lymphocytic leukemia patients]
SO - Genetika 2001 Nov;37(11):1530-7
AD - Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, 119991 Russia.
Deletions in the region located between the STS markers D13S1168 and D13S25 on chromosome 13 are the most frequent genomic changes in patients with B-cell chronic lymphocytic leukemia (B-CLL). After sequencing of this region, two novel candidate genes were identified: C13orf1 (chromosome 13 open reading frame 1) and PLCC (putative large CLL candidate). Analysis of the repeat distribution revealed two subregions differing in composition of repetitious DNA and gene organization. The interval D13S1168-D13S319 contains 131 Alu repeats accounting for 24.8% of its length, whereas the interval GCT16C05-D13S25, which is no more than 180 kb away from the former one is extremely poor in Alu repeats (4.1% of the total length). Both intervals contain almost the same amount of the LINE-type repeats L1 and L2 (20.3 and 21.24%, respectively). In the chromosomal region studied, 29 Alu repeats were found to belong to the evolutionary young subfamily Y, which is still capable of amplifying. A considerable proportion of repeats of this type with similar nucleotide sequences may contribute to the recombinational activity of the chromosomal region 13q14.3, which is responsible for its rearrangements in some tumors in humans.
UI - 11754201
AU - Oliveira GB; Pereira FG; Metze K; Lorand-Metze I
TI - Spontaneous apoptosis in chronic lymphocytic leukemia and its relationship to clinical and cell kinetic parameters.
SO - Cytometry 2001 Dec 15;46(6):329-35
AD - Hematology-Hemotherapy Center, State University of Campinas, Campinas, Brazil.
Chronic lymphocytic leukemia (CLL) presents considerable variability in clinical presentation as well as in its evolution. In contrast to the inhibition of apoptosis in vivo, spontaneous apoptosis after short-term culture occurs. We studied the degree of this apoptosis in vitro, and its interactions with several clinical and laboratory parameters. Apoptosis was measured by the annexin V technique. Proliferation rate was evaluated by the AgNOR (nucleolar organizer regions) technique. There were inverse correlations between the percentage of annexin V-positive cells and peripheral lymphocyte count (r = - 0.49), Rai stage (r = - 0.40), Binet stage (r = - 0.50), TTM (total tumor mass score; r = - 0.51), and percentage of cells with one AgNOR cluster (r = - 0.45). Direct correlations were found with hemoglobin values ( r = 0.34) and platelet counts (r = 0.52). The number of CD8-positive cells showed a correlation with peripheral lymphocyte count (r = 0.49). When this variable was held constant, a correlation was detected between CD8-positive cells and staging (r = -0.47), TTM (r = - 0.42), and platelet count (r = 0.67). CD4-positive lymphocytes presented a correlation only with CD8-positive lymphocytes. In a cluster analysis, it was possible to create three groups of patients with different apoptosis rates using the TTM and AgNOR values. We conclude that, with the progression of the disease, together with the increase of tumor mass and proliferation rate, there is a decrease in the susceptibility to apoptosis. Copyright 2001 Wiley-Liss, Inc.
UI - 11754202
AU - Hendrickx A; Bossuyt X
TI - Quantification of the leukocyte common antigen (CD45) in mature B-cell malignancies.
SO - Cytometry 2001 Dec 15;46(6):336-9
AD - Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.
CD45 is a glycoprotein expressed on all lymphohematopoietic cells. Its expression increases during normal B-cell differentiation and remains stable on mature cells. Although it is widely known that CD45 antigen expression is decreased in B-acute lymphocytic leukemia (ALL), only scarce and contradictory information is available on CD45 expression on mature B-cell malignancies. In healthy adults (n = 15), CD45 expression on B lymphocytes was lower than that on T cells. In patients with chronic lymphocytic leukemia (CLL; n = 22), CD45 expression on malignant cells was lower than that on the whole lymphocyte population of healthy adults (n = 28) and on normal B lymphocytes (n = 15). In 6 of the 22 CLL patients, the malignant cell population could be separated from the normal lymphocyte population on the CD45-side scatter (SSC) plot. In 16 CLL patients, there was some degree of overlap between the malignant and normal cells with respect to CD45 expression. For these patients, there was an inverse correlation between CD45 expression on the whole lymphocyte population and the percentage of malignant cells in this population. In two patients with mantle cell lymphoma (MCL), CD45 expression on the malignant cells appeared lower than that on normal B cells and on the whole lymphocyte population. In six patients with hairy cell leukemia (HCL), CD45 expression on hairy cells was comparable to that on the whole lymphocyte population of healthy adults, but slightly higher than that of normal B cells. Evaluation of CD45 expression may help to characterize mature B-cell malignancies. Copyright 2001 Wiley-Liss, Inc.
UI - 11781259
AU - Adinolfi E; Melchiorri L; Falzoni S; Chiozzi P; Morelli A; Tieghi A;
TI - Cuneo A; Castoldi G; Di Virgilio F; Baricordi OR P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia.
SO - Blood 2002 Jan 15;99(2):706-8
AD - Department of Experimental and Diagnostic Medicine, Section of Medical Genetics and General Pathology, University of Ferrara, Italy.
Human leukocytes express a receptor for extracellular nucleotides, named P2X7R, that in lymphocytes can either mediate cell death or proliferation, depending on the level of activation. The authors have investigated P2X7R expression and function in 21 patients affected by B-cell chronic lymphocytic leukemia, 13 with an evolutive and 8 with an indolent variant of the disease. Resting cytoplasmic Ca++ concentration was significantly higher in lymphocytes from patients with the evolutive compared with indolent variant. Furthermore, in the former, P2X7R stimulation triggered a Ca++ influx significantly larger. Higher Ca++ influx correlated with an increased P2X7R expression in the lymphocytes from patients with the evolutive form. Finally, incubation in the presence of extracellular adenosine triphosphate decreased spontaneous proliferation of lymphocytes from patients affected with the evolutive variant but had no effects on lymphocytes from patients with the indolent form. These results suggest that expression and function of P2X7R may correlate with the severity of B-cell chronic lymphocytic leukemia.
UI - 11799965
AU - Anether G; Marschitz I; Tinhofer I; Greil R
TI - Interleukin-15 as a potential costimulatory cytokine in CD154 gene therapy of chronic lymphocytic leukemia.
SO - Blood 2002 Jan 15;99(2):722-3
UI - 11697653
AU - Hercher C; Robain M; Davi F; Garand R; Flandrin G; Valensi F; Vandeputte
TI - H; Albert A; Maynadie M; Troussard X; Simon GH; Lespinasse J; Portefaix G; Merle-Beral H; The Groupe Francais d'Hematologie Cellulaire A multicentric study of 41 cases of B-prolymphocytic leukemia: two evolutive forms.
SO - Leuk Lymphoma 2001 Sep-Oct;42(5):981-7
AD - Service d'Hematologie Biologique, C.H.U. Pitie-Salpetriere Hospital, Paris, France.
B-prolymphocytic leukemia (B-PLL) is an infrequent disease with a poor prognosis. We present the clinical and biological features of 41 patients. Median age was 67 years [42-89] and male-female sex ratio was 2.4. The immunophenotyping revealed B-cell phenotype, with a high level expression of surface IgM and/or IgD in all cases, FMC7+ in 76 % of cases and CD5+ in 67%. Marked spontaneous in-vitro apoptosis was observed in most cases tested (n = 12). The median overall survival time was 5 years and the event-free survival time was 37 months. As detected by univariate and multivariate analysis, the only variables associated with a poor prognosis were advanced age and anemia. No significant difference was observed between de novo PLL (n = 27) and prolymphocytoid transformation of chronic lymphocytic leukemia (n = 14). Two groups of patients were individualized according to their clinical course: patients who died within one year of diagnosis (n = 14) and patients who had a prolonged survival (n = 23) without any treatment in some cases. The comparison between the 2 groups showed that they differed in age (p = 0.01) and anemia (p = 0.02). We also observed that the patients with p53 mutations had a worse clinical outcome. Taken together these data confirm that B-PLL should be regarded as a distinct form of chronic lymphoproliferative disorder and suggest the existence of two patterns of clinical evolution.
UI - 11426546
AU - Kolb JP; Roman V; Mentz F; Zhao H; Rouillard D; Dugas N; Dugas B; Sigaux
TI - F Contribution of nitric oxide to the apoptotic process in human B cell chronic lymphocytic leukaemia.
SO - Leuk Lymphoma 2001 Jan;40(3-4):243-57
AD - U365 INSERM, Institut Curie, Paris, France. firstname.lastname@example.org
B cell chronic lymphocytic leukaemia (B-CLL) is characterised by defective apoptosis that cannot be explained solely on the basis of the known chromosomal abnormalities. We and other have now reported that the leukemic cells spontaneously display the inducible isoform of nitric oxide synthase, iNOS. Inhibition of the iNOS pathway leads to increased apoptosis of the tumoral cells in vitro, indicating that the endogenous release of NO contributes to their resistance to the normal apoptotic process. The factors that induce the expression of iNOS in vivo in the leukemic cells are not yet identified. Yet, as interaction of B-CLL leukemic cells with bone marrow stromal cells promotes their survival, the involvement of adhesion molecules and integrins may be suspected. The engagement of CD23 stimulates iNOS activation in the tumoral cells, suggesting that in vivo interaction of CD23 with one of its recognised ligands may contribute to iNOS induction. A role for CD40-CD40 ligand interaction may also be hypothesised. The mechanisms involved in the anti-apoptotic role of NO are not fully understood, but may implicate the inhibition of caspase activity, hence the impairment of the Fas pathway. In addition, the mitochondrial membrane potential disruption appears to be a NO-sensitive step in the apoptosis cascade. The presence of a NOS displaying anti-apoptotic properties has now been recognised in different cell types, including various leukaemia. A better knowledge of the mechanisms governing the ultimate fate of NO, anti- versus pro-apoptotic would allow the development of new therapeutic approaches for the treatment of these diseases.
UI - 11426562
AU - Mainou-Fowler T; Proctor SJ; Dickinson AM
TI - Gamma-linolenic acid induces apoptosis in B-chronic lymphocytic leukaemia cells in vitro.
SO - Leuk Lymphoma 2001 Jan;40(3-4):393-403
AD - University Department of Haematology, School of Clinical, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.
Gamma linolenic acid (GLA) is cytotoxic to many types of human cancer cells. Most chemotherapeutic agents are cytotoxic by inducing apoptosis. We examined the apoptotic activity of GLA on purified B-cells isolated from patients with B-cell chronic lymphocytic leukaemia (B-CLL) and from normal individuals. GLA significantly increased the degree of apoptosis in B-CLL B-cells after 24 hours of culture. The mean percentage of cells undergoing apoptosis when cultured in medium alone (spontaneous apoptosis) was 20% (range: 7 to 31%) (n=25) and in the presence of GLA (5 microg-60 microg) was: 42%-95%. In the presence of GLA 5 microg/ml and dexamethasone the degree of apoptosis was 86% (range: 72 to 100%). GLA induced apoptosis in B-CLL B-cells at a higher level than that observed with normal B-cells at all lower concentrations tested 5, 10 and 15 microg/ml: P=0.045; 0.027 and 0.022, respectively. At 30 microg/ml of GLA, no significant difference in the percentage of cells displaying apoptosis between B-CLL and normal B-cells was observed (P=0.075). GLA induced apoptosis in B-CLL T-cells at both 10 and 30 microg/ml. The degree of apoptosis in normal T-cells with GLA was also significant at the higher concentration of 30 microg/ml. Interleukin 4 (IL4), a viability factor in B-CLL, and vitamin E, an anti-oxidant, protected B-CLL B-cells against GLA (20 microg/ml)-induced apoptosis. These results demonstrate that GLA induces apoptosis in B-CLL B- and T-cells cells in vitro and that they are more susceptible to GLA-induced apoptosis than normal peripheral blood B- and T-cells.
UI - 11572760
AU - Yonetani N; Ueda C; Akasaka T; Nishikori M; Uchiyama T; Ohno H
TI - Heterogeneous breakpoints on the immunoglobulin genes are involved in fusion with the 5' region of BCL2 in B-cell tumors.
SO - Jpn J Cancer Res 2001 Sep;92(9):933-40
AD - First Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
The 5' flanking region of the BCL2 gene (5'-BCL2) is a breakpoint cluster of rearrangements with immunoglobulin genes (IGs). In contrast to t(14;18)(q32;q21) affecting the 3' region of BCL2, 5'-BCL2 can fuse to not only the heavy chain gene (IGH), but also two light chain gene (IGL) loci. We report here cloning and sequencing of a total of eleven 5'-BCL2 / IGs junctional areas of B-cell tumors, which were amplified by long-distance polymerase chain reaction-based assays. The breakpoints on 5'-BCL2 were distributed from 378 to 2312 bp upstream of the translational initiation site and, reflecting the alteration of regulatory sequences of BCL2, 5'-BCL2 / IGs-positive cells showed markedly higher levels of BCL2 expression than those of t(14;18)-positive cells. In contrast, the breakpoints on the IGs were variable. Two 5'-BCL2 / IGH and two 5'-BCL2 / IGLkappa junctions occurred 5' of the joining (J) segments, suggesting operation of an erroneous variable (V) / diversity (D) / J and V / J rearrangement mechanism. However, two other 5'-BCL2 / IGH junctions affected switch regions, and the kappa-deleting element, which is located 24 kb downstream of the constant region of IGLkappa, followed the 5'-BCL2 in another case. One 5'-BCL2 / IGLkappa and two 5'-BCL2 / IGLlambda junctions involved intronic regions where the normal recombination process does not occur. In the remaining one case, the 5'-BCL2 fused 3' of a Vlambda gene that was upstream of another Vlambda / Jlambda complex carrying a non-producing configuration, indicating that the receptor editing mechanism was likely involved in this rearrangement. Our study revealed heterogeneous anatomy of the 5'-BCL2 / IGs fusion gene leading to transcriptional activation of BCL2, and suggested that the mechanisms underlying the formation of this particular oncogene / IGs recombination are not identical to those of t(14;18).
UI - 11705880
AU - Yamauchi T; Nowak BJ; Keating MJ; Plunkett W
TI - DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine.
SO - Clin Cancer Res 2001 Nov;7(11):3580-9
AD - Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
PURPOSE: Chronic lymphocytic leukemia (CLL) lymphocytes respond to DNA alkylation by excision repair, with the extent of repair increasing as the cells acquire resistance to alkylating agents. Because incorporation of nucleotide analogues into the repair patches elicits death signals in quiescent cells, the increased capacity for excision repair in alkylator-resistant cells could facilitate incorporation of nucleotide analogues. We hypothesized that the mechanism-based interaction of nucleoside analogues with alkylating agents could elicit greater than additive killing of CLL cells. EXPERIMENTAL DESIGN: Lymphocytes from 50 patients with CLL that were not refractory to alkylators were treated in vitro with 4-hydroperoxycyclophosphamide (4-HC) with or without prior incubation with fludarabine nucleoside (F-ara-A) or with clofarabine (Cl-F-ara-A). DNA damage repair kinetics were determined by the single-cell gel electrophoresis (comet) assay. Cytotoxicity was assessed by staining with annexin V. RESULTS: CLL lymphocytes promptly initiated and completed excision repair in response to 4-HC. A 2-h preincubation with 10 microM F-ara-A or 10 microM Cl-F-ara-A inhibited the repair initiated by 4-HC, with inhibition peaking at the intracellular concentrations of 50 microM F-ara-ATP or 5 microM Cl-F-ara-ATP. Combining 4-HC with either F-ara-A or Cl-F-ara-A produced more than additive apoptotic cell death than the sum of each alone. The increase in cytotoxicity was proportional to the initial magnitude of the DNA incision and to the extent of repair inhibition by the nucleoside analogues, suggesting close correlation between the repair inhibition and induction of cell death. CONCLUSIONS: DNA repair, which is active in CLL lymphocytes, may be a biological target for facilitating the incorporation of nucleoside analogues and increasing their cytotoxicity. Thus, the increased repair capacity associated with resistant disease may be manipulated to therapeutic advantage.
UI - 11587207
AU - Robak T; Blonski JZ; Kasznicki M; Gora-Tybor I; Dwilewicz-Trojaczek J;
TI - Boguradzki P; Konopka L; Ceglarek B; Sulek J; Kuliczkowski K; Wolowiec D; Stella-Holowiecka B; Skotnicki AB; Nowak W; Moskwa-Sroka B; Dmoszynska A; Calbecka M Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.
SO - Leukemia 2001 Oct;15(10):1510-6
AD - Department of Hematology, Medical University, Lodz, Poland.
The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.
UI - 11587209
AU - Casanova B; de la Fuente MT; Garcia-Gila M; Sanz L; Silva A;
TI - Garcia-Marco JA; Garcia-Pardo A The class II tumor-suppressor gene RARRES3 is expressed in B cell lymphocytic leukemias and down-regulated with disease progression.
SO - Leukemia 2001 Oct;15(10):1521-6
AD - Departamento de Inmunologia, Centro de Investigaciones Biologicas, CSIC, Madrid, Spain.
The molecular pathogenesis of B cell chronic lymphocytic leukemia (B-CLL), the most common form of leukemia, remains unknown. We have used the mRNA differential display technique to analyze genes that may be involved in the development/progression of B-CLL. We have identified the tumor suppressor retinoic acid receptor responder 3 (RARRES3) as a B-CLL-related gene. RARRES3 maps to chromosome band 11q23, a region frequently deleted in lymphoproliferative disorders. To assess the potential involvement of RARRES3 in leukemogenesis, we examined 24 cases of B-CLL, 10 of acute lymphocytic leukemia (ALL) and five related cell lines by RT-PCR and sequence analyses. We report a correlation between RARRES3 down-regulation and B-CLL progression. We also found decreased RARRES3 gene levels in ALL cases and in the five cell lines studied. We did not find mutations in any of the leukemia samples assayed, including those with 11q23 deletion. These results indicate that RARRES3 may play a role in B-CLL progression.
UI - 11587214
AU - Siegmund B; Welsch J; Loher F; Meinhardt G; Emmerich B; Endres S; Eigler
TI - A Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis.
SO - Leukemia 2001 Oct;15(10):1564-71
AD - Division of Clinical Pharmacology, Medizinische Klinik Innenstadt, Klinikum of the Ludwig-Maximilians-University Munich, Germany.
B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.
UI - 11783506
AU - Gora-Tybor J; Lech-Miranda E; Blonski JZ; Robak T
TI - 2-chlorodeoxyadenosine (2-CdA) does not change the expression of Fas antigen on chronic lymphocytic leukaemia cells.
SO - Adv Exp Med Biol 2000;486():307-10
AD - Department of Hematology, University of Lodz, Poland.
UI - 11783511
AU - Marinello E; Carlucci F; Rosi F; Tabucchi A
TI - Purine nucleotide metabolism in chronic lymphocytic leukemia lymphocytes.
SO - Adv Exp Med Biol 2000;486():339-42
AD - Institute of Biochemistry and Enzymology, Nuovi Istituti Biologici, Siena, Italy.
UI - 11783518
AU - Marinello E; Rosi F; Tabucchi A; Carlucci F; Cinci G; Coli M; Floridi A;
TI - Fini C Extraction and purification of ecto-5'-nucleotidase from human lymphocytes.
SO - Adv Exp Med Biol 2000;486():373-6
AD - Institute of Biochemistry and Enzymology, University of Siena, Italy.
UI - 11781620
AU - Nieto Y; Bearman SI; Shpall EJ; Jones RB; Cagnoni PJ; Rabinovitch RA;
TI - McSweeney PA Intensive chemotherapy for progressive chronic lymphocytic leukemia administered early after a nonmyeloablative allograft.
SO - Bone Marrow Transplant 2001 Dec;28(11):1083-6
AD - University of Colorado Bone Marrow Transplant Program, Denver, CO 80262, USA.
A 51-year-old patient with refractory CLL elected to participate in a trial of nonmyeloablative trans- plantation from an HLA-matched unrelated donor. He received low-dose fludarabine/TBI, with infusion of donor PBPC and cyclosporin (CsA)/MMF. Early post transplant he experienced explosive tumor growth with respiratory insufficiency. After immunosuppression discontinuation and rituximab administration, no response was observed. This prompted treatment with cyclophosphamide (2 g/m(2)/day x 2), paclitaxel (250 mg/m(2) over 24 h), doxorubicin (50 mg/m(2)), solumedrol (500 mg/day), and a second dose of rituximab, from days +11 to +14. A rapid response was achieved. Chemotherapy did not cause an obvious compromise of donor stem cell engraftment or establishment of stable donor chimerism.
UI - 11786937
AU - Nestler U; Deinsberger W; Grumbrecht S; Kuchelmeister K; Boker DK
TI - CLL cells in a brain metastasis of bronchial adenocarcinoma in a patient with three different neoplasms - case report.
SO - Zentralbl Neurochir 2001;62(2):57-61
AD - Neurochirurgische Klinik, Justus-Liebig-Universitat, Giessen. email@example.com
OBJECTIVE: We report the case of a patient with three different malignancies who had a brain metastasis of bronchial adenocarcinoma with infiltrates of CLL lymphocytes and who had been operated for prostate cancer years before. - PATIENT AND RESULTS: A 72-year-old man was admitted to our department after a Jacksonian seizure. The MRI showed a left temporal mass lesion. The patient was suffering from chronic lymphocytic leukemia (CLL) for ten years, he had had surgery for prostate cancer eight years ago and the diagnosis of bronchial carcinoma was made during preoperative routine diagnostics. After neurosurgical intervention the histologic examination of the cerebral mass lesion disclosed metastasis of a PSA-negative adenocarcinoma with perivasal infiltrates of lymphocytic leukemic cells. - DISCUSSION: There are few reports about patients with three primary malignancies. CLL may play a role in enabling tumor cells to escape the immune response and could facilitate development of the prostate cancer and of a bronchial adenocarcinoma as secondary cancers in this patient. The combined occurrence of adenocarcinoma cells and CLL lymphocytes in the brain metastasis can be explained by impairment of the blood-brain-barrier in the carcinoma metastasis enabling extravasation of circulating leukemic cells.
UI - 11865846
AU - Wong KF; So CC; Chan JK
TI - Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia.
SO - Am J Clin Pathol 2002 Feb;117(2):246-51
AD - Department of Pathology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
Chronic lymphoproliferative disorders sometimes can be difficult to classify. We report 4 cases characterized by large cells with distinct central nucleoli, reminiscent of prolymphocytic leukemia, but shown on further workup to represent mantle cell lymphoma. At initial examination, the patients had generalized lymphadenopathy, splenomegaly, and a leukemic blood picture. The peripheral blood showed many large cells with round to slightly irregular nuclei, single central nucleoli, and a fair amount of pale cytoplasm. The picture was not typical of prolymphocytic leukemia because of the presence of generalized lymphadenopathy and the large size of the circulating abnormal cells. Immunophenotypic study showed that the large lymphoid cells were CD5+ CD23- mature B cells with overexpression of cyclin D1, and cytogenetic study demonstrated the translocation t(11;14)(q13;q32) in 3 patients. Lymph node biopsy confirmed a diagnosis of mantle cell lymphoma, pleomorphic variant, in all 4 patients. This study documents the existence of an unusual leukemic form of mantle cell lymphoma with prominent nucleoli; the clinicopathologic features that distinguish it from other chronic lymphoproliferative disorders are discussed.
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