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PubMed1999

In vitro evaluation of B-CLL cells apoptotic responses to irradiation.

Defective apoptosis is a mechanism which could possibly explain B chronic lymphocytic leukemia (B-CLL) cell accumulation. Differences in evolution and prognosis of B-CLL patients may be due to heterogeneity in apoptotic cell death. We studied the apoptotic response to in vitro gamma radiation of blood mononuclear cells from 18 untreated B-CLL patients. In cells irradiated with 2, 4 or 8 Gy and then cultured for 20 hours, the percentage of trypan blue excluding (viable) cells was not modified (>92%). An apoptotic response to irradiation was detected in the majority of the patients, but the individual percentage of apoptotic cells varied widely (8 to 81% after 8 Gy irradiation) in individual cases. The flow cytometric analysis of nick-end DNA labeling demonstrated a dose effect of irradiation, particularly in patients with an apoptotic response of over 20%. In the future, a valuable clue to the selection of irradiation regimens for B-CLL patients may be the investigation of correlations between in vitro radiation-induced apoptosis and the in vivo response to radiation therapy.

Aged↗

PubMedDate not supplied

A human B-cell CLL model established by transplantation of JOK-1 cells into SCID mice and an anti-leukemia efficacy of fludarabine phosphate.

The present study was carried out to establish a human chronic lymphocytic leukemia (CLL) mouse model by transplantation of a JOK-1 human CLL cell line into SCID (severe combined immunodeficient) mice and to examine anti-leukemic effects of fludarabine phosphate, a prodrug of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2F-ara-A). In vitro cytotoxic screening pattern of 2F-ara-A differed from those of other anticancer agents. Intraperitoneal inoculation with JOK-1 cells in SCID mice allowed the cells to infiltrate into a variety of organs including the liver and thymus, and resulted in the death of the mice with a median survival time of 29.5 days, associated with hepatomegaly, splenomegaly and enlarged lymph nodes. The ascitic cells expressing the human B-lymphocytic cell surface antigen CD19 actually grew after a latent period of 15 days. In this model, twice daily administration of fludarabine phosphate at a dose of 135 mg/kg for 5 days prolonged the survival time of the mice for considerably longer period than once-a-day treatment. Fludarabine phosphate in the doubled course of twice daily increased life span of 32.9%, which was in a similar range to that of doxorubicin. Thus, intraperitoneal inoculation of the human JOK-1 CLL cells into SCID mice seems to serve as an animal model potentially for human leukemia, suggesting that transplantation and subsequent infiltration processes of human CLL cells is useful measures to explore mechanistic aspects for drug-induced modulation of the tumor progression.

Animals↗

PubMed2006

[Molecular biology of CLL].

Recently, major advances have occurred in our understanding of the biology of chronic lymphocytic leukemia (CLL). CD5-positive CLL cells were once assumed to originate from immature, immunologically incompetent B lymphocytes, and to passively accumulate due to increased life time. In 1999, two research groups demonstrated that CLL, which is a morphologically uniform but clinically heterogenous disease, can be classified into two major subgroups on the basis of the mutational status of the immunoglobulin heavy chain (IgH) genes. It was also suggested that these two groups both originate from mature cells that have passed the antigen selection process. This hypothesis was confirmed by gene expression studies indicating a uniform pattern characteristic to memory cells, as well as specific B-cell receptor (BCR) structures supporting the existence of a functional antigen selection. The differences in the BCR signal transduction mechanisms may underlie the different clinical behavior in which zeta-associated tyrosine kinase (ZAP-70) may play a pivotal role, since elevated ZAP-70 expression is likely to be an unfavorable prognostic factor in CLL. The diagnostic testing for ZAP-70 expression plays an important role in the therapeutic decisions.

Gene Expression Regulation, Enzymologic↗

PubMed1978

Purine nucleoside phosphorylase in chronic lymphocytic leukemia (CLL).

Purine nucleoside phosphorylase (PNP), the enzyme schematically next to adenosine deaminase in the purine salvage pathway, has been demonstrated cytochemically in peripheral blood lymphocytes of healthy subjects and chronic lymphocytic leukemia (CLL) patients. The enzyme activity is confined to the cytosol. In healthy subjects the majority of lymphocytes are strongly reactive for PNP, whereas the rest are devoid of cytochemically demonstrable activity. The percentage of PNP-positive cells largely corresponds to the number of E rosette-forming cells and is inversely proportional to the number of Ig-bearing cells. In six of seven CLL patients studied only a minor percentage of the lymphocytes showed strong PNP activity, whereas the large majority (88%--98%) possessed trace activity. Such patients have a high number of Ig-bearing cells and a low number of E rosette-forming cells. A different pattern of markers was found in the lymphocytes of the seventh CLL patient: 66% were strongly reactive for PNP, an important number formed E rosettes, and a minor percentage were Ig bearing. These data indicate that PNP can be useful as a "nonmembrane" marker in the differentiation of the B and T cell origin in CLL and deserves to be studied in other lymphoproliferative disorders.

Histocytochemistry↗

PubMed1976

Complement receptors (C3b, C4b/C3d) unbalance on CLL lymphocytes.

A study of lymphocytes bearing C3b, C4b and C3d complement receptor (CRL) was performed on human peripheral blood from 16 healthy donors and 12 patients affected with Chronic Lymphatic Leukemia (CLL). In the latter group a clear rise of C3dCRL was demonstrated, when compared with immunoadherence receptors bearing lymphocytes. However, when compared with controls, also these latter were slightly augmented. Furthermore in CLL under treatment CRL populations showed the same profile as CLL: so it was suggested that the treatment reduced not selectively all the three types of CRL, within the population of sIg bearing lymphocytes. Here we discuss the hypothesis that, in CLL, the proliferating lymphocytes population is chiefly sIg+, C3d+/C3b-, C4b-, but also sIg+, C3d+/C3b+, C4b+.

Animals↗

PubMed2002

Efficient gene transfer of CD40 ligand into primary B-CLL cells using recombinant adeno-associated virus (rAAV) vectors.

B cells of chronic lymphocytic leukemia (B-CLL) are resistant to transduction with most currently available vector systems. Using an optimized adenovirus-free packaging system, recombinant adeno-associated virus (rAAV) vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and CD40 ligand (AAV/CD40L) were packaged and highly purified resulting in genomic titers up to 3 x 10(11)/mL. Cells obtained from 24 patients with B-CLL were infected with AAV/EGFP or AAV/CD40L at a multiplicity of infection (MOI) of 100 resulting in transgene expression in up to 97% of cells as detected by flow cytometry 48 hours after infection. Viral transduction could be specifically blocked by heparin. Transduction with AAV/CD40L resulted in up-regulation of the costimulatory molecule CD80 not only on infected CLL cells but also on noninfected bystander leukemia B cells, whereas this effect induced specific proliferation of HLA-matched allogeneic T cells. Vaccination strategies for patients with B-CLL using leukemia cells infected ex vivo by rAAV vectors now seems possible in the near future.

Adult↗

PubMed2004

Determination of the in vivo effects of cladribine alone and its combination with cyclophosphamide or cyclophosphamide and mitoxantrone on Bax and Bcl-2 protein expression in B-CLL cells.

The present study investigated a correlation between expression of Bcl-2 family members, Bax and Bcl-2 (the Bax/Bcl-2 ratio values) in B-CLL cells in vivo and the response of these cells to chemotherapy. Western blot technique combined with videodensitometry was used for Bax and Bcl-2 determination in homogenate, nuclear and postnuclear fractions of mononuclear cells isolated from peripheral blood of B-CLL patients treated with cladribine alone (C), and in combination with cyclophosphamide (CC) or mitoxantrone and cyclophosphamide (CMC). The Bax/Bcl-2 ratio values were changed in B-CLL cells originated from blood samples of patients treated by the three therapy protocols, and was the most elevated in the case of CMC treatment. High degree of B-CLL cell apoptosis induction with cladribine combined with mitoxantrone and cyclophosphamide was confirmed by DNA fragmentation and an appearance of apoptotic morphology among leukemic cells from the blood of patients treated with this form of combined therapy.

Aged↗

PubMed1991

Expression of interleukin-1 alpha, interleukin-1 beta and interleukin-6 in chronic B lymphocytic leukaemia (B-CLL) cells from patients at different stages of disease progression.

We have previously found that isolated B-CLL cells from progressive disease produce less interleukin-1 beta (IL-1 beta) as compared with cells from patients with indolent disease. Here we extend that finding to include measurements of IL-1 beta mRNA and secretion of IL-1 alpha and interleukin-6 (IL-6). As before, a lower production of IL-1 beta was found in cells from progressive disease. IL-6 was produced by cells from patients at all stages, with a tendency to follow the IL-1 beta production. Low secretion of IL-1 alpha was noted. When viable cells were permeabilized and analysed at the single cell level with monoclonal antibodies, most B-CLL cells were found to contain IL-1 alpha. A minor fraction of non-permeabilized cells expressed IL-1 alpha at the cell membrane. However, only small fractions of cells were positive for intracellular IL-1 beta (less than 1%) and almost no IL-6-positive cells were found. We conclude that either IL-1 beta and IL-6 are produced by a minor population of undefined cells, or that a more sensitive in situ method is needed to detect production of these cytokines in B-CLL cells. The possible biological significance of secreted, and membrane-expressed helper factors in B-CLL is discussed.

Adult↗

PubMed1990

The experience of the French Cooperative Group in the treatment of CLL.

This paper summarizes results from clinical trials of the French Cooperative Group in chronic lymphocytic leukemia, CLL 80 and CLL 85 protocols. These protocols were based on the (A, B, C) classification. Nine hundred and seventy three patients were randomised in the CLL 80 protocol, 612 in stage A, 289 in stage B and 72 in stage C. Results from the fourth interim analysis were (1) in stage A, overall survival was better in the untreated group as compared to patients treated by daily chlorambucil with an increased incidence of epithelial cancers in the chlorambucil group; (2) in stage B, there was no improvement in overall survival with the COP regimen as compared to daily chlorambucil; (3) in stage C, the effectiveness of the CHOP regimen was confirmed. More than 1,400 patients have been randomised in the CLL 85 protocol but results from the first interim analysis were only available in stage B (194 patients). At the 6-month evaluation 28% reached complete remission in the CHOP group versus 12% in the chlorambucil-prednisone group. More follow-up is needed to assess the benefit from the CHOP regimen in terms of survival in stage B patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

A further characterization of B-CLL lymphocytes: phenotypic and functional studies.

The CLL-B lymphocytes are characterized by the surface expression of B cell markers (CD19, CD20, HLA-DR) and of a low intensity IgM. The presence of T antigens (CD5, CD1) may be related either to the activation stage of these cells, either to their origin from a distinct B subset. In contrast, the detection of B5, CD25, CD71 and CD38 activation markers clearly demonstrated that the B-CLL lymphocyte is a preactivated or activated cell, at various phases of the cellular cycle. Functional studies revealed that B-CLL lymphocytes are susceptible to the effects of several interleukins (BCGF(s), IL2, IFN alpha). The inhibition of the response to IL2 by IL4 has important implications for the potential use of cytokines in the management of B-CLL patients.

Antigens, Surface↗

PubMed1987

Proliferation patterns of peripheral blood lymphocytes in CLL patients: cytophotometric and microfluorimetric study.

Peripheral blood lymphocytes of 19 patients with CLL, 9 patient with LS and 10 healthy donors were studied by Feulgen cytophotometry, 3HTdR autoradiography, A0 microfluorimetry and PHA stimulated cultures. In CLL the bulk of cells are in G0 (80.6 +/- 3.7%) the rest are in G1 (16.3 +/- 3.6%) and S + G2 (3.0 +/- 1.0%). Thymidine LI values were two orders lower (0.098 +/- 0.04). In five cases combined autoradiographic and cytophotometric study on the same cells revealed 6-14% of cells arrested in S. In peripheral blood of LS patients G0 cells also predominate, and only in 3 cases cytophotometry revealed hyperdiploid (S + G2) cells. In normal lymphocytes 1.5 hrs after PHA stimulation A0 binding increases on the average by 80% compared to unstimulated cultures and remains at this level during 12 hrs. CLL and LS cells behave nearly the same with the only difference: the 80% increase is observed only after 3-4.5 hrs in culture. G0----G1 flow rate in case of normal lymphocytes is higher than for neoplastic cells but both are recruited into cell cycle during all the period in culture. G1----S transition is delayed in case of LS lymphocytes and strongly inhibited in CLL lymphocyte cultures compared to normal cells. The possible mechanisms of these features are discussed.

Adult↗

PubMed1987

Cell membrane fluidity in chronic lymphocytic leukemia (CLL) lymphocytes and its relation to membrane receptor expression.

Cell membrane fluidity (CMF), Ig receptor expression and ecto-ATPase activity were investigated in lymphocytes from patients with chronic lymphocytic leukemia (CLL) and from healthy controls. Significant differences were observed in the parameters of individual CLL cases as compared to normal controls. These findings suggest that malignant transformation of lymphocytes to CLL cells is accompanied by disturbances in cell membrane structure and function, which can be modulated to some extent by exogenous influences on the lipid composition of the cell membrane. The results also suggest, however, that CLL is apparently an inhomogeneous disease with major variations in the investigated parameters among individual cases.

Adenosine Triphosphatases↗

PubMed1988

An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL.

Most CLL cases correspond to proliferation of a B-cell clone characterized by: low amounts of surface Ig (SIg); presence of receptors for mouse red blood cells; expression of a 67 Kd antigenic determinant (CD5) initially described to be a pan-T cell antigen. These peculiar characteristics differentiate the CLL B lymphocyte from B lymphocytes proliferating in other B-cell malignancies. These so-called CD5 + B cells constitute a minority of B cells in adults, although they predominate during foetal life. This latter fact induced a majority of authors to assume that CLL B lymphocytes correspond to proliferation of an immature B-cell clone. However, this hypothesis does not explain the particular high frequency with which hypogammaglobulinemia and autoimmune phenomena directed against blood cell components are found in B-CLL, as well as the difficulty to include CD5 antigen in most differentiation pathways of B-cells. In this work, we shall discuss the available evidence coming from Ly 1-B cells (mouse counterpart of CD5 B cells), indicating that these cells correspond to a separate B lineage. We shall also discuss the evidence for hypogammaglobulinemia being mainly a B cell defect caused by dilution or inhibition of normal CD5 negative B cells and disordered autoimmunity as a consequence of a disturbance of the idiotypic network, which normally antagonizes autoimmune clones.

Agammaglobulinemia↗

PubMed1987

Does the CLL B lymphocyte correspond to expansion of an immature B clone or to expansion of a distinct subpopulation of B cells?

Most CLL cases correspond to proliferation of a B-cell clone characterized by (1) low amounts of SmIg, (2) the presence of receptors for mouse red blood cells, (3) the presence of a 67-kd antigenic determinant recognized by CD5 monoclonal antibodies, also present in normal T cells, (4) the ability of these cells to differentiate in vitro, and (5) the ability at least for some clones to differentiate and secrete immunoglobulins in vivo. The normal counterpart to this B-cell clone corresponds to a small subpopulation of lymphocytes, present at the edge of the germinal center in human lymph nodes. Interestingly, this subpopulation appears to constitute a substantial part of the B-cell population in 20-week-old fetal lymph nodes and spleen. These results have induced most authors to assume that the CLL B lymphocyte corresponds to proliferation of an immature B-cell clone, arrested at an intermediate stage between pre-B cells and mature B cells. However, this hypothesis does not explain the high frequency with which hypogammaglobulinemia and autoimmune hemolytic anemia are found in B CLL. In this work, we discuss the possibility that the CLL B lymphocyte corresponds to proliferation of a B-cell line, whose counterpart in the mouse is the Ly1 B, Lyb5+ subpopulation.

Animals↗

PubMed1988

Cyclosporin A in the treatment of CLL associated PRCA and bone marrow hypoplasia.

Three patients (1 PRCA-T-CLL, 1 PRCA-B-CLL, 1 B-CLL aplasia) were treated with cyclosporin A (CS-A). Patient no 1 had relapsed during steroid therapy and the remaining two patients had been resistant to conventional immunosuppression. CS-A produced in all cases a prompt remission (within 1-4 weeks) of bone marrow failure. Mild reversible renal toxicity was the only side-effect noted. CS-A might be tried in every case of CLL-associated bone marrow failure.

Adult↗

PubMedDate not supplied

Immunological identification of peripheral-blood lymphocytes from patients with lymphoproliferative disorders in Nigeria. II. Chronic lymphocytic leukaemia (CLL).

The surface markers for blood T and B lymphocytes in sixteen consecutively diagnosed patients with CLL were sought for. There were twelve females and four males, and their ages ranged from 30 to 70 years. Although the absolute numbers of T and B lymphocytes were increased, the percentage scores as well as mitogenic responses of these leukaemic cells were depressed, and all the patients except one who has T-cell CLL were considered to have Null-cell CLL. This finding suggests that CLL may take an unusual form in a tropical environment, and this may account for the long remissions which often occur.

Adult↗

PubMed1982

Monoclonal CLL B-cells may be induced to grow in an in vitro B-cell colony assay system.

A simple reproducible in vitro B-cell colony assay system was used to evaluate B-cell growth in controls and patients with chronic lymphocytic leukemia (CLL). All six CLL patients studied formed B-cell colonies. The number of colonies was significantly less in patients than controls (66 +/- 18 versus 127 +/- 8). CLL colonies were shown to be monoclonal and appeared to reflect the circulating malignant B-cell clone in our patient group, while the six controls studied formed polyclonal B-cell colonies. Wright-Giemsa staining showed typical plasma cells to have developed in the controls but not in the patients. Cells from CLL patients retained a more lymphoid appearance. It is believed that investigations with this B-cell assay will provide the means for further in vitro evaluation of malignant B-cell proliferation in other lymphoproliferative disorders.

B-Lymphocytes↗

PubMedDate not supplied

Fludarabine in untreated and previously treated B-CLL patients: a report on efficacy and toxicity.

BACKGROUND: It has been shown that fludarabine (FLU) is superior to conventional treatment in B-CLL for rate and quality of response, leading to CR even at the molecular level. In this paper we report our preliminary results with this drug in B-CLL patients. METHODS AND PATIENTS: Twenty-seven B-CLL patients (16 refractory to previous therapy, 7 responsive and treated for subsequent disease reexpansion, 4 untreated with active disease) were administered FLU at a dose of 25 mg/sqm for 5 days every 4 weeks. RESULTS: Twenty-five patients were evaluable and 14 of them (56%) were responsive. All four untreated patients responded: 1 CR (PCR analysis showed the persistence of clonal VDJ rearrangement) and 3 PR, while 67% of the previously responsive group again showed a reaction: 2 PR (33%) and 2 nodular PR (33%). Among the refractory patients we recorded 6 responses (39%): 1 CR (6%) and 5 PR (33%). Besides 2 cases of lethal myelotoxicity, we observed 2 cases of encephalopathy and 2 cases of heart failure. Four deaths may have been related to FLU therapy (15%). CONCLUSIONS: We confirm the effectiveness of FLU and the improved outcome, in terms of toxicity and response rate, it provides in untreated B-CLL patients. Further studies are needed to explore the possible negative effects of FLU on neuronal and heart function, and the impact of this drug on survival in selected groups of patients.

Adult↗