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PubMed2004

Imatinib sensitizes CLL lymphocytes to chlorambucil.

The effect of imatinib on chlorambucil (CLB) cytotoxicity in chronic lymphocytic leukemia (CLL) lymphocytes was examined in vitro. Imatinib sensitizes the WSU and I83 human CLL cell lines, 10- and two-fold, respectively, to CLB. Furthermore, in primary cultures of malignant B-lymphocytes obtained from 12 patients with CLL (seven patients were untreated and five treated with CLB), imatinib synergistically sensitized these lymphocytes from two- to 20-fold to CLB. This synergistic effect was observed at concentrations of imatinib (</=10 microM), which are achievable in patients with minimal toxicity. Moreover, the combination of both drugs results in increased apoptosis in CLL cell lines. These results suggest that imatinib should be useful in improving the therapeutic index of CLB in CLL. The mechanism of action appears to involve imatinib inhibition of c-abl kinase activity with an associated decrease in CLB-induced Rad51 phosphorylation and CLB-induced Rad51 nuclear foci, suggesting that imatinib decreases Rad51-related DNA repair of CLB-induced DNA lesions. Altogether, our results suggest that imatinib is a promising adjuvant therapy to CLB treatment of CLL.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL.

Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-delta is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL. Blockade of protein kinase C-delta (PKC-delta) by the highly specific inhibitor rottlerin induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. By co-culturing bone marrow stromal and CLL cells, we determined that the proapoptotic effect of rottlerin is not abolished in the presence of survival factors, indicating that a targeted therapy against PKC-delta might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and non-mitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death. Herein we report that the inhibition of PKC-delta decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Deltapsi. In addition, we discovered that ZAP-70-expressing cells are significantly more susceptible to rottlerin-induced cell death than ZAP-70 negative cells. We finally observed that rottlerin can augment cell toxicity induced by standard chemotherapeutic drugs. Conclusively, PKC-delta is a promising new target in the combat against CLL.

Acetophenones↗

PubMed1997

p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis.

To determine the role of the p53 gene in chronic lymphocytic leukaemia (CLL) and its possible involvement in the pathogenesis of a progressive form of CLL characterized by > 10%, prolymphocytes (CLL/PL), we selected 32 cases, 17 with typical morphology and 15 CLL/PL. The extent of inactivation of p53 was examined by assessing loss of heterozygosity (LOH) at 17p13.3, by sequencing the highly conserved region (exons 5-9) of the p53 gene and by analysing p53 protein expression. LOH was detected in 8/28 (29%) cases, p53 mutations in 5/32 (16%) cases and p53 expression in 5/27 (19%) cases. Overall 11 cases (30%) had p53 abnormalities of which eight cases had CLL/PL. There was a significant association between CLL/PL and p53 abnormalities (P=0.05); 75% of cases with LOH, 80% of p53 mutations and 80% of cases positive for p53 protein had CLL/PL. Thus, p53 inactivation is the first gene abnormality identified so far to be involved in the development of CLL/PL. All the cases with typical CLL and p53 abnormalities had only one allele affected whereas 4/6 CLL/PL had both alleles inactivated. This difference in the extent of p53 inactivation suggests that accumulation of p53 abnormalities may be associated with progression of CLL to CLL/PL. CLL cases with p53 abnormalities were characterized by a higher incidence of stage C (P<0.025), a higher proliferative rate (P=0.05), short survival (P<0.005) and resistance to first-line therapy (P<0.02) but not to nucleoside analogues. Analysis of the correlation between p53 status and incidence of trisomy 12 by fluorescence in situ hybridization (FISH) showed that trisomy 12 was more frequent in cases without p53 abnormalities, suggesting that trisomy 12 and p53 may represent different pathways of transformation in CLL.

Blotting, Southern↗

PubMed2003

Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL).

One fifth of B-cell chronic lymphocytic leukaemia (B-CLL) patients exhibit loss of heterozygosity (LOH) at 10q23.3, the site of the tumour suppressor PTEN. Microsatellite markers mapped complete LOH to 10q23.3 in 2/41 B-CLL (5%) and allelic imbalances in 6/41 (15%). No PTEN gene mutations were found. PTEN protein expression was not detected in 11 B-CLL (28%), and was reduced in eight patients (20%). LOH or allelic imbalances at 10q23.3 were fairly frequent in B-CLL, but did not encompass the PTEN gene. Nevertheless, PTEN protein may be absent in B-CLL with a normal PTEN genotype, suggesting a role of this phosphatase in the molecular pathology of B-CLL.

Allelic Imbalance↗

PubMed2006

Generation of in vitro B-CLL specific HLA class I restricted CTL responses using autologous dendritic cells pulsed with necrotic tumor lysate.

New approaches in the treatment of chronic B lymphocytic leukemia (B-CLL) have led to improved clinical response rates. In this setting there is a need to evaluate novel therapeutic approaches that aim to eradicate minimal residual B-CLL cells following an initial favorable response. The use of tumor lysate-pulsed dendritic cells (DC) represents a potentially important development in the field of cancer vaccination. B-CLL is ideally suited for DC-based vaccination since tumor cells are readily available (peripheral blood) and both known (tumor idiotype) and unknown antigens can be exploited to stimulate immune responses. In the current study we have evaluated the ability to stimulate in vitro autologous immune reactivity against target B-CLL cells using autologous DCs pulsed with B-CLL tumor lysate. Enhanced specific T cell IFN-gamma expression was detected in 9 of 14 patients evaluated. These responses were specific with increased levels of IFN-gamma mRNA measurable in T-cells stimulated with NC-DCs and not unpulsed DCs or DCs pulsed with normal B cell lysate. CTLs demonstrating increased levels of IFN-gamma mRNA also lysed autologous B-CLL targets cells in an MHC class 1-restricted manner by (51)chromium release assay. Priming target leukemic cells with CD40 ligand and IL-4 enhanced CTL killing. The effector CTL displayed negligible toxicity against NK susceptible target cells K-562 and spared CD19(+)CD5(-) normal B cells in cytotoxicity assays. The specificity of the CTL response was confirmed by blocking HLA class I molecules and cold target inhibition assays.

Cell Differentiation↗

PubMed1990

Monoclonal antibodies against Epstein-Barr virus transformed B lymphocytes from a CLL patient.

Immunization of BALB/c mice with EBV-CLL-1 cells, derived from Epstein-Barr virus transformed B lymphocytes from a chronic lymphocytic leukemia (CLL) patient, yielded 2 monoclonal antibodies (IgG1 Kappa and IgG2a Kappa) against a membrane antigen on a subset of normal B lymphocytes and non-Hodgkin's lymphomas. Immunofluorescence revealed strong reactivity of the antibodies with EBV-CLL-1 cells and with most lymphocytes in tonsil follicles, in the intestinal wall, around splenic arterioles and near Hassall's corpuscles in the neonatal thymus as well as with a small proportion of lymphocytes in some large reactive lymph node follicles, weak reactivity with 1/5 of peripheral blood B lymphocytes (PBL), and no reactivity with platelets, granulocytes and non-lymphoid tissues. PBL from 3 CLL patients showed weak staining of only larger cells. Intense fluorescence was observed in several non-Hodgkin's lymphomas of various histological types and in Burkitt's lymphoma lines but not in the 3 T lymphoblastoid and 12 nonlymphoid tumor lines examined. The antibodies precipitated Mr 22,000 and 33,000 bands from surface labeled RAJI or EBV-CLL-1 cells and cross-competed in a binding inhibition assay. The antibodies had approximately 6 million binding sites per EBV-CLL-1 or RAJI cell but were not cytotoxic. This high antigen-density and limited expression in normal cells may permit their use for immunocytological diagnosis and targeting cytotoxic agents and radionuclides against appropriate lymphoma cells.

Animals↗

PubMed2004

Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis.

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare. We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells. The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.

Aged↗

PubMed2006

Pattern and distribution of immunoglobulin VH gene usage in a cohort of B-CLL patients from a Northeastern region of Italy.

We analyzed individual VH gene rearrangements in 55 consecutive B-chronic lymphocytic leukemia (B-CLL) patients collected from a northeastern region of Italy, stressing the possible differences related to geographic characteristics of the cohorts studied. Considering the percentage of somatic mutations present in the VH gene sequences and using the 98% cut-off value, 38 of the 55 B-CLL (69%) patients displayed somatic hypermutations and 17 (31%) had a germline configuration. Our results confirm and extend the observations of a bias in the use of certain VH, DH, and JH genes among B-CLL cells. The most frequently used VH genes were VH1-69 (12.7%) with VH3-23 (12.7%) and VH4-34 (10.9%). Collectively these genes accounted for 36.3% of the cases. In the mutated cases, the range of mutations varied from 2% to 15%, with a median of 6.5%. VH1-69 (7 cases, all unmutated) carried few mutations as opposed to VH3-23 (7 cases, 5 of which mutated), VH4-34 (6 cases, all mutated), and VH3-30 (5 cases, all mutated), which show a high load of mutations. D3 family genes were found frequently (38.1%) followed by D2 (27.2%) and D6 (18.1%). The individual D segment most frequently used was D3-3, which was present in 16.3% of cases. There was predominance of the JH4 gene (49%) followed by JH6 (40%). Analysis of the distribution of replacement and silent mutations in the mutated sequences using the method of Lossos showed in 39.4% of cases evidence of antigen selection in the framework region and/or complementary determining regions. In comparison with a recent study on B-CLL patients from the Mediterranean area, the VH4-34 gene was significantly overused in the mutated group at a percentage double that of the Italian cohort reported in this study (10.9% vs. 5%), but at a frequency similar to the entire Mediterranean region (10.7%). We also found an over-representation of VH1-69 usage in the germline group, at a frequency (12.7%) higher than previously described by the same authors (Italian 8%, Mediterranean 10.7%). On the contrary, VH3-07 and VH3-49 were not much used in our study (5.4% and 1.8%, respectively) compared with the Italian group (8% and 5.1%). In our study, VH3-23 gene segment was frequently expressed, at frequency as high as that of VH1-69, a finding in keeping with reported B-CLL Italian data, but higher than the entire series of the Mediterranean area (12.7% vs. 9.2%); VH3-21 gene, frequently expressed in northern European CLL but rarely in the Mediterranean area, was completely absent. This biased usage of VH family genes may reflect a geographic leukemic repertoire, perhaps owing to a peculiar genetic background, depending on variations in germline composition of the IgVH locus or to the effect of a potential environmental element less frequently encountered in different regions.

Aged↗

PubMed2002

MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

B-Cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic lymphoma (SLL) consists of heterogeneous diseases that are distinguished by morphological, immunophenotypic and molecular features. MUM1 (multiple myeloma oncogene 1) is a protooncogene that is deregulated as a result of (6;14)(p25;q32) chromosomal translocation in multiple myeloma, and is also expressed in a variety of malignant lymphoma entities. We examined the expression of MUM1 in B-CLL / SLL, and found that 2 of 4 B-CLL-derived cell lines and 14 of 29 patients' specimens expressed MUM1 by immunohistochemical analysis. MUM1 expression was not associated with CD38 expression, somatic hypermutation of immunoglobulin heavy chain gene variable region (IgV(H)), or any other clinical characteristics of the patients. Interestingly, the patients who were positive for MUM1 showed shorter overall survival times than those who were negative for MUM1 (50% survival: 22 months vs. 82 months) (P = 0.0008, log-rank test). Multivariate analysis by Cox's proportional-hazards regression model showed that MUM1 expression and unmutated IgV(H) status were independent unfavorable prognostic factors in patients with B-CLL / SLL. These findings suggest that MUM1 expression is a useful prognostic factor in B-CLL / SLL. The biological role and mechanism of action of MUM1 in B-CLL / SLL need to be clarified for the development of therapies for patients with the poor prognostic subtype.

ADP-ribosyl Cyclase↗

PubMed1991

Increased spontaneous secretion of IL-6 from B cells of patients with B chronic lymphatic leukaemia (B-CLL) and autoimmunity.

We studied B cells from 18 patients with B-CLL, six of them with autoimmune haemolytic anaemia, for spontaneous secretion of IL-6. Our aim was to determine whether the increased incidence of autoimmune disease found in B-CLL patients is associated with enhanced spontaneous IL-6 secretion. IL-6 was measured by the effect of B cell supernatants on the proliferation of an IL-6 dependent plasmacytoma cell line T1165. The highest IL-6 values (7.4 +/- 1.8 U/ml) were measured in supernatants derived on day 3 of culture from lymphocytes of the six patients with B-CLL and concomitant autoimmune disease. The maximal IL-6 values for 10 patients with B-CLL only were 2.8 +/- 0.3 U/ml and for 10 age-matched controls, 0.8 +/- 0.3 U/ml (P less than 0.01, each group compared with the other). We conclude that there is an association between B-CLL, autoimmune disease and the spontaneous in vitro secretion of IL-6. Further studies are needed to determine whether the IL-6 secretion plays a role in the pathogenesis of autoimmune disease in patients with B-CLL.

Aged↗

PubMed1993

Modulation and high frequency expression of autoantibody-associated cross-reactive idiotypes linked to the VHI subgroup in CD5-expressing B lymphocytes from patients with chronic lymphocytic leukaemia (B-CLL).

Leukaemic B cells from patients with chronic lymphocytic leukaemia (B-CLL) are known to express the pan T-cell marker CD5 and a restricted set of immunoglobulin (Ig) variable region heavy (VH) and light (VL) chains encoded by germline or minimally mutated germline genes. We have studied surface expression of certain VH and VK gene products on peripheral blood B lymphocytes from 23 patients with B-CLL, using a panel of monoclonal antibodies (MoAbs) recognizing germline encoded cross-reactive idiotypes (CRI) associated with VHI (G6, G8), VHIII (B6, D12), VKIIIb (17-109) and an epitope linked to the VKIII light chain subgroup (C7). While only 1.7-3.2% of peripheral blood B lymphocytes from normal individuals expressed the VHI-associated CRI (VHI-CRI), these CRI were expressed on virtually all the leukaemic B cells from 17-22% of the CLL patients. The VHIII-associated CRI (VHIII-CRI), however, were found in 8.5-13% of the CLL B cells. Fifty per cent of the IgMK-expressing CLL cells (7/14) expressed the VKIII light chain subgroup of which only one expressed the VKIIIb-associated CRI (VKIIIb-CRI), 17-109. The anti-VHI-associated CRI antibodies were used to study their regulatory effect on in vitro Ig synthesis by the leukaemic cells. A significant suppression of spontaneous and mitogen-driven Ig production was observed in all cases studied. These results demonstrate an over-expression of VHI and VKIII gene products in B-CLL and suggest that B cells expressing these CRI are particularly susceptible to lymphoproliferative stimuli. The anti-CRI antibodies can be used to modulate Ig production by the leukaemic cells and may be of potential value for selective immunotherapy.

Aged↗

PubMed2004

Intracellular IFN-gamma expression by CD3+/CD8+ cell subset in B-CLL patients correlates with stage of the disease.

Changes in the cytokine network may be responsible for malignant cell accumulation in B-cell chronic lymphocytic leukaemia (B-CLL). Among different cytokines of question interferon gamma (IFN-gamma) is indicated to prevent malignant cells from entering apoptosis. The aim of the study was to determine IFN-gamma production capacity of T-cell subsets and B lymphocytes in B-CLL patients in comparison with healthy individuals and during disease progression. Forty patients with newly diagnosed, untreated B-CLL and 20 healthy individuals were studied. The two- and three-colour flow cytometry techniques were used to detect intracellular cytokine expression. We detected statistically significantly higher percentage of both CD3+/CD4+/IFN-gamma+ and CD3+/CD8+/IFN-gamma+ in patients than in controls (P < 0.001 in both cases). Moreover the percentage of CD3+/CD8+/IFN-gamma+ cells correlated with stage of the disease (R = 0.39, P = 0.01) and parameters of disease progression like lymphocyte count and total tumour mass score (R = 0.33, P = 0.03 and R = 0.31, P = 0.04, respectively). By contrast, the percentage of CD19+/IFN-gamma+ cells in B-CLL group was lower than in controls (P < 0.01). These findings indicate that T-cell populations rather than malignant B cells are the source of IFN-gamma in B-CLL patients. The subset of CD3+/CD8+ cells expressing IFN-gamma seems to play a special role in the disease progression and more precise investigation should elucidate its role as a prognostic marker in B-CLL and a target for therapeutic strategies.

Antigens, CD19↗

PubMed1998

Spectral morphometric characterization of B-CLL cells versus normal small lymphocytes.

Spectral morphometric characterization of typical chronic lymphocytic leukemia (B-CLL) cells vs normal small lymphocytes stained by May-Grunwald-Giemsa was carried out by multipixel spectral imaging. The light intensity (450-850 nm of 10(4) pixels) from nuclear domains of each stained cell was recorded and represented as light transmittance spectra and optical density. Transmitted light spectra of two nuclear domains were determined, one with low-intensity light transmittance (LIT) and the other with high-intensity light transmittance (HIT). A spectral library was constructed using the four transmitted light spectra representing the HIT and LIT domains of the normal human lymphocytes and the LIT and HIT domains of the CLL cells. The spectral library served to scan CLL lymphocytes from 10 cases of CLL and the lymphocytes of 10 healthy individuals. Each spectrally similar domain in the nuclei of the lymphocytes was assigned an arbitrary color. The morphometric analysis of the spectrally classified nuclei showed specific spectral patterns for B-CLL in 92% of the cells. The specific spectral characteristics of each of the two cell populations were also observed by their optical density light absorbance spectra. We propose that spectral morphometric analysis may serve as an additional diagnostic tool for detection of CLL lymphocytes in a hematological specimen.

Cell Nucleus↗

PubMed2003

The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays.

B-cell chronic lymphoid leukemia (BCLL) is a highly heterogeneous human malignancy, presumably reflecting specific molecular alterations in gene expression and protein activity that are thought to underlie the variable disease outcome. Most B-CLL cell samples undergo apoptotic death in response to DNA damage. However, a clinically distinct aggressive subset of B-CLL is completely resistant in vitro to irradiation-induced apoptosis. We therefore addressed 2 series of microarray analyses on 4 sensitive and 3 resistant B-CLL cell samples and compared their gene expression patterns before and after apoptotic stimuli. Data analysis pointed out 16 genes whose expression varied at least 2-fold specifically in resistant cells. We validated these selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) on 7 microarray samples and confirmed their altered expression level on 15 additional B-CLL cell samples not included in the microarray analysis. In this manner, in 11 sensitive and 11 resistant B-CLL cell samples tested, 13 genes were found to be specific for all resistant samples: nuclear orphan receptor TR3, major histocompatibility complex (MHC) class II glycoprotein HLA-DQA1, mtmr6, c-myc, c-rel, c-IAP1, mat2A, and fmod were up-regulated, whereas MIP1a/GOS19-1 homolog, stat1, blk, hsp27, and ech1 were down-regulated. In some cases, the expression profile may be dependent on the status of p53. Some of these genes encode general apoptotic factors but also exhibit lymphoid cell specificities that could potentially be linked to the development of lymphoid malignancies (MIP1alpha, blk, TR3, mtmr6). Taken together, our data define new molecular markers specific to resistant B-CLL subsets that might be of clinical relevance.

Apoptosis↗

PubMed2003

Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells.

Recently, it was demonstrated that transfection of dendritic cells (DCs) with tumor-derived RNA can elicit effective T-cell responses. This technique does not require the definition of the tumor antigen or HLA haplotype of the patients. We applied this approach to induce HLA class I- and class II-restricted T-cell responses directed against malignant cells from patients with chronic lymphocytic leukemia (B-CLL). Here, we show that DCs generated from monocytes of patients with B-CLL induce leukemia-specific cytotoxic and proliferative T-cell responses on transfection with total RNA isolated from autologous leukemic B lymphocytes. Standard 51Cr-release assays showed specific major histocompatibility complex (MHC) class I-restricted cytotoxic activity against the autologous leukemic B cells and DCs transfected with CLL-RNA, whereas nonmalignant B cells were spared. The specificity of the cytotoxic T-lymphocyte (CTL) response was confirmed using cold target inhibition assays and by blocking HLA class I molecules. Furthermore, we established a protocol for the amplification of whole B-CLL mRNA. The use of DCs transfected with in vitro amplified B-CLL mRNA elicited specific T-cell responses similar to the results obtained with native mRNA. These data suggest that vaccinations using DCs transfected with RNA might be a potent new strategy in the treatment of CLL.

Antigens, CD19↗

PubMed2004

CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival.

This work addresses the question whether CD38, a negative prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL), plays a role in neoplastic B-cell growth and survival. We show that CD38+ B-CLL cells bind to murine fibroblasts transfected with the CD31 ligand. The interaction triggers an extensive remodeling of the B-CLL membrane, with relocalization of BCR/CD19 to the CD38/CD31 contact areas, and it also increases cell survival and proliferation. A second event is the up-modulation of the survival receptor CD100, restricted to proliferating cells, and a concomitant decrease of CD72 (low-affinity CD100 ligand and negative regulator of immune responses). The most efficient signals are delivered through sequential interactions between CD38/CD31 and CD100/plexin-B1 (high-affinity CD100 ligand), as inferred by coculture experiments using specific transfectants and blocking monoclonal antibodies (mAbs). The finding that nurselike cells from B-CLL patients express CD31 and plexin-B1, which deliver growth and survival signals to CD38+/CD100+ B-CLL cells, further confirms the model proposed. These findings show that a set of normal receptors and ligands ruling physiologic signaling pathways in B lymphocytes becomes detrimental when expressed in the context of B-CLL cells, ultimately leading to the generation of a tumor reservoir.

ADP-ribosyl Cyclase↗

PubMed2005

CLL, but not normal, B cells are dependent on autocrine VEGF and alpha4beta1 integrin for chemokine-induced motility on and through endothelium.

Vascular endothelial cell growth factor (VEGF) is a multifunctional cytokine involved in tumor formation. In chronic lymphocytic leukemia (CLL), it is known that the malignant cells secrete VEGF and possess VEGF receptors. This suggests that an autocrine loop might be important in the pathogenesis of CLL. Here we show that, in patients with lymphadenopathy, autocrine VEGF and alpha(4)beta(1) integrin are involved in the chemokine-dependent motility of CLL cells on and through endothelium-processes important for the invasion of lymphoreticular tissues, a major determinant of disease outcome. In contrast, normal lymphocytes were not dependent on autocrine VEGF or alpha(4)beta(1) for either type of cell movement. Moreover, in contrast to normal B lymphocytes, CLL cells failed to cluster and activate alpha(L)beta(2) in response to chemokines, unless VEGF receptor(s) and alpha(4)beta(1) were also engaged by their respective ligands. This is the first demonstration that autocrine VEGF is involved in CLL-cell motility, and that the alpha(L)beta(2) on the malignant cells is functionally altered compared with that of normal B cells in not undergoing activation in response to chemokine alone. Given the importance of cell motility for tissue invasion, the present results provide a rationale for a trial of VEGF and alpha(4) blockade in patients with CLL who have tissue disease.

B-Lymphocytes↗

PubMed2005

ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL).

Molecular markers like IgV(H) mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70(+) CLL B cells respond in vitro more readily than ZAP-70(-) CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70(+) CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-alpha, a survival factor produced by stromal cells) compared with ZAP-70(-) cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70(+) but not ZAP-70(-) CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70(+) disease.

Case-Control Studies↗