Autoantigenic Targets of B-Cell Receptors (BCR) Derived From Chronic Lymphocytic Leukemias Bind to and Induce Proliferation of Leukemic Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2884-2884
Author(s):  
Klaus-Dieter Preuss ◽  
Gerhard Held ◽  
Natalie Fadle ◽  
Evi Regitz ◽  
Maria Kemele ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Specific Binding ◽  
Cell Receptor ◽  
Convincing Evidence ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Long Time ◽  
First Time

Abstract Abstract 2884 Background Auto-antigenic targets of the B-cell receptor (BCR) derived from malignant cells in chronic lymphocytic leukemia (CLL) might play a role in the pathogenesis of this neoplasm. Patients and Methods In order to identify autoantigenic targets of CLL-derived BCR we screened human tissue-derived protein macroarrays with Fab fragments obtained by papain treatment of CLL cells derived from 50 consecutive cases. Antigens were biochemically and molecularly characterized and recombinantly expressed. Results An autoantigenic target was identified for 12/50 (24%) of the cases, with 3 autoantigens being the target of the BCR from two patients each. CLL-BCR derived from the same stereotype subset recognized the same antigen, but differed epitopes. By flow cytometry using flag-tagged recombinantly expressed autoantigens binding of antigen to the surface of CLL was demonstrated, which was specific for the CLL cells from which the BCR used for the identification of the respective autoantigen was derived. Moreover, binding of the autoantigen to the respective leukemic cells induced specific activation as shown by increased cytoplasmic calcium concentration, induced MYC expression and proliferation of leukemic CLL cells as demonstrated by a proliferation assay (EZ4U). Conclusions Autoantigens are frequent targets of CLL-derived BCR. Their specific binding to and induction of proliferation in respective leukemic cells, which has been demonstrated for the first time, provide the most convincing evidence to date for the long-time hypothesized role of autoantigens in the pathogenesis of chronic lymphocyte leukemia. Supported by Sander-Stiftung (Munich, Germany) Disclosures: No relevant conflicts of interest to declare.

Evidence for Autostimulatory Mechanisms in Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2880-2880
Author(s):  
Martin Trepel ◽  
Fabian Muller ◽  
Mareike Frick ◽  
Janina Rahlff ◽  
Claudia Wehr ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phage Display ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Specific Binding ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Fab Fragment

Abstract Abstract 2880 Background: The development and / or course of chronic lymphocytic leukemia (CLL) may be driven by the recognition of antigens through the B cell receptor (BCR). While it has been recognized that the diversity of epitope recognition may be astonishingly confined in CLL, knowledge on antigens recognized by CLL BCRs is still limited. Here, we identified and characterized an epitope recognized by a defined CLL BCR which may broaden our view on potential mechanisms of antigenic drive in CLL. Methods: The B- cell receptor of a random CLL-patient was cloned and expressed as Fab fragment in E.coli. Random phage display reptile litanies we skeletal on the immobilized Fab and landed peptides were tested for specific binding. Specific clones we sequenced and sequences were analyzed for homology to known proteins. Recognition of candidate proteins was verified in brooding assays or recombinant proteins. Results: Screening random phage display peptide libraries, we identified a CLL BCR epitope mimic that displayed a high degree of homology to a conserved peptide string in the variable region of immunoglobulin heavy and light chains. CLL BCR binding to this epitope as well as binding to full length heavy and light immunoglobulin chains was verified by binding assays and a protein array screening. Interestingly, the CLL BCR also interacted with itself, as the identified epitope was also present in its own primary amino acid sequence. Conclusions: These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. As the peptide mimicking this immunoglobulin epitope is known to be recognized by BCRs of other CLL cases in addition to the index case investigated here, such autostimulatory mechanisms may be relevant to a large number of CLL patients. Disclosures: No relevant conflicts of interest to declare.

High ZAP-70 and Differential Expression of B-Cell Receptor Related Genes in Chronic Lymphocytic Leukemia with V3-21 Gene Usage.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 773-773
Author(s):  
Dirk Kienle ◽  
Alexander Kröber ◽  
Dirk Winkler ◽  
Daniel Mertens ◽  
Annett Habermann ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Bcr Signaling ◽  
Gene Usage ◽  
Lower Expression

Abstract V3-21 gene usage defines a distinct genetic subgroup of chronic lymphocytic leukemia (CLL) characterized by a poor clinical outcome regardless of the VH mutation status. V3-21 cases exhibit a highly characteristic B-cell receptor (BCR) structure as demonstrated by homologous CDR3 sequences and a restricted use of VL genes implicating a common antigen involved in tumor pathogenesis of this specific CLL subgroup. To investigate the role of antigenic stimulation in the pathogenesis of V3-21 using CLL, we analyzed the quantitative expression of genes involved in BCR signaling (ZAP-70, SYK, BLNK, LYN, PI3K, PLCG2, FOS), B-cell activation (TRAF3, STAT6, NFKB), and cell cycle or apoptosis control (ATM, BCL-2, BAX, CDK4, CCND1, CCND2, CCND3, p27, E2F1, MYC) in V3-21 cases in comparison to VH mutated (VH MUT) and VH unmutated (VH UM) cases not using the V3-21 gene. To obtain native expression signatures we studied a non-CD19-purified (nPU) cohort (V3-21: 18 cases, equally divided into VH mutated and VH unmutated cases; VH MUT: 17; VH UM: 19) and, for verification, a CD19-purified (PU) cohort (V3-21: 10 cases, equally divided into VH mutated and unmutated; VH MUT: 12; VH UM: 16) to exclude a contamination of the results by non-tumor cells. All cases were analyzed by FISH for +3q, 6q-, +8q, 11q-, +12q, 13q-, 17p-, and t(11;14) to avoid major imbalances of genomic alterations between the subgroups under study. As expected, ZAP-70 expression was higher in VH UM as compared to VH MUT cases in the nPU (p=0.007) as well as the PU cohort (p=0.009). V3-21 cases showed a higher ZAP-70 expression as compared to VH MUT (nPU: p=0.033; PU: p=0.038). This applied also when restricting this comparison to V3-21 mutated cases (nPU: p=0.018). Median ZAP-70 expression in the PU cohort was 1.15 in VH MUT vs. 7.69 in VH UM cases, as compared to 7.05 in V3-21 cases (V3-21 mutated cases: 10.69; V3-21 unmutated: 6.7). Other genes differentially expressed between the V3-21 and VH MUT subgroups in nPU cases were PI3K (p=0.048), PLCG2 (p=0.007), CCND2 (p=0.003), p27 (p=0.003), BCL-2 (p=0.025), and ATM (p=0.006). In addition, a set of genes was detected with a differential expression between V3-21 and VH UM (nPU) including PLCG2 (p=0.014), NFKB (p=0.023), CCND2 (p=0.001), p27 (0.002), and BAX (p=0.028). Notably, except for ZAP-70, all of the differentially expressed genes showed a lower expression in V3-21 as compared to the other subgroups. When comparing the V3-21 mutated and V3-21 unmutated subgroups (nPU), there were no significant gene expression differences except for CDK4, which showed a lower expression in V3-21 unmutated cases. Therefore, cases with V3-21 usage appear to show a rather homogeneous gene expression pattern independently of the VH mutation status, which can be distinguished from VH MUT and VH UM cases not using V3-21. The expression differences observed suggest a role of differential BCR signaling in the pathogenesis of this distinct CLL subgroup. Deregulation of cell cycle, apoptosis, and candidate genes such as ATM indicate the involvement of additional pathways in the pathogenesis of CLL cases using V3-21.

Involvement of PKC-δ in the Regulation of Notch2 in B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4990-4990
Author(s):  
Rainer Hubmann ◽  
Markus Duechler ◽  
Martin Hilgarth ◽  
Susanne Schnabl ◽  
Josef D. Schwarzmeier ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Negative Selection ◽  
Cell Receptor ◽  
Immunoglobulin M ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Mobility Shift ◽  
Bcr Signaling ◽  
Electrophoretic Mobility Shift Assays

Abstract We have recently shown that NOTCH2 signaling is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia (B-CLL) cells (Hubmann et al., BLOOD 2002). There is an increasing evidence that NOTCH2 plays a determining role in the development/homeostasis of self-reactive CD5+ B-cells, suggesting a potential function of NOTCH2 in B-cell leukemogenesis. Here we study the regulation of NOTCH2 signaling in B-CLL cells and its possible function in B-lymphocytes using NOTCH2 transduced BL41 cells as a model system. Cultured B-CLL samples (n=30) lose their nuclear NOTCH2 (N2IC) activity within one day as demonstrated by electrophoretic mobility shift assays (EMSA). However, DNA-bound NOTCH2 complexes could be maintained in culture by exposure to the phorbolester TPA and is accompained by increased cell viability. The effect of TPA is prevented by the PKC-δ inhibitor Rottlerin indicating that PKC-δ is involved in the regulation of NOTCH2 signaling in B-CLL cells. The activity of N2IC in the leukemic cells appeared to be resistant to the γ-secretase inhibitors DAPT and compound E, two substances known to block ligand mediated release of the NOTCH2 intracellular domain (N2IC). Since B-CLL cells are locked in an anergic state, we next asked whether NOTCH2 modulates B-cell receptor (BCR) signaling and found that retrovirally transduced N2IC rescues the B-cell line BL41 from surface immunoglobulin M (sIgM) mediated apoptosis, a mechanism proposed to prevent the uncontrolled expansion of self-reactive CD5+ B-cells. In summary, our data suggest that B-CLL cells express an activated form of NOTCH2 which might be involved in the protection of the malignant clone from peripheral negative selection.

Stereotyped Subset #4 In Chronic Lymphocytic Leukemia Is Associated With Distinct Gene and Microrna Transcriptional Profile

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1616-1616
Author(s):  
Francesco Maura ◽  
Laura Mosca ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
Marta Lionetti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mirna Expression ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Distinct Gene ◽  
Mirna Expression Pattern

Abstract Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the monoclonal accumulation of B lymphocytes and a variable clinical course. Specific B-Cell Receptor (BCR) utilized by leukemic cells may influence disease progression and outcome. Highly homologous BCR, “stereotyped BCR”, are expressed in a recurrent fraction of patients with CLL and in some cases they were associated with distinct biological and clinical features. Stereotyped subset #4 have been reported to exhibit a favorable clinical course and to be the most frequent stereotyped BCR among the IGHV mutated (IGHV-M) cases. In this study we performed a comprehensive clinical, biological and molecular characterization of leukemic cells from 16 patients utilizing stereotyped subset #4 BCR (IGHV4-34) among a representative prospective cohort of 462 Binet stage A CLL patients enrolled in O-CLL1 protocol (clinicaltrial.gov identifier NCT00917540). In all cases, biological and molecular analyses were performed in peripheral CD19+ B-cells. All subset #4 patients were characterized by lower CD38 expression, unique IGHV-M configuration and absence of NOTCH1 and SF3B1 mutations. None subset #4 patients showed unfavorable cytogenetic deletions (i.e del11q23 and del17p13). Gene expression profiling (GEP) analysis was performed on 217 patients, including 9 subset #4 cases for whom RNA material was available. Supervised analysis comparing subset #4 vs all other patients (208) revealed 14 differentially expressed genes. Furthermore subset #4 patients were characterized by a significant downregulation of WDFY4, MEF2A and upregulation of PDGFA, FGFR1 and TFEC genes when compared with the remaining IGHV-M patients. miRNA profiles were analyzed in 229 patients including 10 subset #4 patients for whom RNA material was available. A specific miRNA expression pattern involving the upregulation of miR-497 and miR-29c was found in subset# 4 cases. Furthermore, we demonstrated that transfection of the miR-497 mimic in primary leukemic CLL cells induces, after 48 and/or 72 h, a downregulation of BCL2, known to be a validated target in different solid cancers. Our data provide a contribution to the biological definition of CLL patients with specific stereotyped IGHV4-34 BCR and identify for the first time distinct gene and miRNA expression profiles associated with this subset, providing further evidence of the putative leading role of HCDR3 conformation in CLL. Disclosures: No relevant conflicts of interest to declare.

Targeting Early Events of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia: Suppressed Syk and PLCγ2 Activities Predict Apoptotic Response of Leukemic Cells to Dasatinib

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5023-5023
Author(s):  
Y. Lynn Wang ◽  
Zibo Song ◽  
Pin Lu ◽  
John P. Leonard ◽  
Morton Coleman ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Bcr Signaling

Abstract B cell receptor (BCR) signaling plays an essential role in the pathogenesis of chronic lymphocytic leukemia. In a subset of patients with a poor clinical outcome, BCR ligation leads to increased cell metabolism and cell survival (Cancer Research66, 7158–66, 2006). Based on these findings, we tested whether targeting BCR signaling with dasatinib, an inhibitor of Src kinase, would interfere with the signaling cascade and cause death of CLL B cells. CLL leukemic cells were isolated from 34 patients and were incubated with or without dasatinib at a low dose of 128 nM. Among 34 cases, viability of leukemic cells was reduced by 2% to 90%, with an average of ~50% reduction on day 4 of ex vivo culture. Further study showed that CLL B cells undergo death by apoptosis via the intrinsic pathway which involves the generation of reactive oxygen species. Analysis of the Src family kinases showed that phosphorylation of Src, Lyn and Hck was inhibited by dasatinib not only in those cases that responded to dasatinib with apoptosis, but also in those that did not respond well (<20% apoptosis). Further analysis revealed that suppressed activity of two downstream molecules, Syk and PLC Statistical analysis showed a significant correlation between CLL dasatinib response and their IgVH mutation and ZAP70 status. Cases with worse prognoses by these criteria have a better response to the kinase inhibitor. Lastly, we have also found that ZAP70 positive cases showed a greater degree of PLC

B-Cell Receptor Configuration and Adverse Cytogenetics Are Associated with Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1780-1780
Author(s):  
Francesco Maura ◽  
Carlo Visco ◽  
Erika Falisi ◽  
Reda Gianluigi ◽  
Sonia Fabris ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Germ Line ◽  
Conflicts Of Interest ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia

Abstract Abstract 1780 Background: Biological features related to the development of autoimmune hemolytic anemia (AHIA) in patients with chronic lymphocytic leukemia (CLL) are crucial insights in the understanding of the pathogenesis of autoimmune phenomena in the course of the disease. Design and Methods: We retrospectively analyzed 585 CLL patients with available immunoglobulin heavy-chain variable (IGHV) gene status and B-cell receptor (BCR) configuration (HCDR3). Of them, 73 developed AIHA. The clinical characteristics at CLL diagnosis and follow-up were available in all patients, while cytogenetic analysis at the time of diagnosis was available in 409 patients. Results: Occurrence of AIHA was significantly associated with an IGHV unmutated (UM) status (p<0.0001) and unfavorable cytogenetic lesions [del(17)(p13) and del(11)(q23)] (p<0.0001). Stereotyped HCDR3 sequences were identified in 173 of 585 patients (29.6%) and were similarly represented among patients developing AIHA (28,7%) or not (29.6%). Of the stereotyped subsets, subset #3 was associated with a significantly higher risk of AIHA occurrence than the other HCDR3 configurations (p=0.004). Restricting the analysis to UM patients, a strong association was found between AIHA and “truly” UM patients, defined as patients carrying a 100% identity with the germ line configuration. Multivariate analysis showed that “truly” UM IGHV, del(17)(p13) and del(11)(q23) were the strongest independent variables associated with risk of developing AIHA (p=0.02, p=0.0002 and p=0.01, respectively). Based on the results of the multivariate analysis, we constructed a risk score of developing AIHA during time, according to the presence of none (low risk = favorable cytogenetics and mutated (M) IGHV), one (intermediated risk = unfavorable cytogenetic or UM), or two (high risk = unfavorable cytogenetic and UM) risk factors. This scoring system allowed a significant patient risk stratification (Figure 1). Conclusions: Taken together, our data indicate that an UM IGHV status and/or unfavorable cytogenetic lesions are associated with the risk of developing secondary AIHA in CLL patients and suggest a possible role of specific stereotyped BCR subsets in a proportion of cases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Cedric Schleiss ◽  
Raphael Carapito ◽  
Luc-Matthieu Fornecker ◽  
Leslie Muller ◽  
Nicodème Paul ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cellular Response ◽  
Ex Vivo ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Ex Vivo Model ◽  
Innovative Therapy

AbstractB-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions.

CLL Biology and Prognosis

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 278-284 ◽  
Author(s):  
Guillaume Dighiero
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Staging Systems ◽  
Cellular Markers ◽  
Major Progress

Abstract Chronic lymphocytic leukemia (CLL) follows an extremely variable course with survival ranging from months to decades. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in CLL patients. In particular, the mutational profile of Ig genes and some cytogenetic abnormalities have been found to be important predictors of prognosis in CLL. However, this progress has raised new questions about the biology and prognosis of the disease, some of which are addressed here. Such questions include: 1) What is the role of the B-cell receptor (BCR) in CLL pathogenesis? 2) Is CLL one disease? 3) Is CLL an accumulative disease? 4) What is the normal counterpart of the CLL B lymphocyte? 5) Have the Rai and Binet staging systems become obsolete? 6) Which is the best surrogate for Ig mutational profiles?

Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia Show Anomalous Lyn Tyrosine Kinase which Contributes to Defective Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1917-1917
Author(s):  
Livio Trentin ◽  
Anna Maria Brunati ◽  
Antonella Contri ◽  
Anna Cabrelle ◽  
Marta Miorin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Cyclosporin A ◽  
B Cell ◽  
B Lymphocytes ◽  
Protein Level ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of mature B lymphocytes in the G0/G1 phase of the cell cycle, expressing B-cell related (i.e. CD19, surface immunoglobulins) and unrelated molecules (CD5 and CD23). The signal transduction pathways underlying the abnormalities of these leukemic cells are poorly understood and no data are available on deregulated cell signalling in B-CLL. Since Lyn activation plays a pivotal role in the signaling cascade triggered by BCR engagement, we investigated whether this kinase may be involved in CLL pathogenesis. In this study, we investigated freshly isolated and purified malignant B cells obtained from 40 CLL patients and we observed that the Src-kinase Lyn, the switch molecule coupling B-cell-receptor to downstream signaling, displays anomalous properties. Western blot and confocal analyses demonstrated that Lyn is overexpressed at the protein level in leukemic cells as compared to normal B-lymphocytes with a substantial aliquot of the kinase anomalously present in the cytosol of leukemic cells. While in normal B lymphocytes Lyn activation is triggered by B-cell-receptor engagement with anti-IgM antibodies, in freshly isolated leukemic cells this kinase is constitutively active and accounts for high basal protein tyrosine-phosphorylation and low responsiveness to IgM-ligation. To address the question of whether the upregulation of Lyn protein and activity plays a role in the defective apoptosis of leukemic cells, we investigated the relationship between Lyn and the cell survival of malignant lymphocytes in the presence of either dexamethazone and cyclosporin A, which are known to induce apoptosis of human lymphocytes, or PP2 and SU6656, which are selective inhibitors of Lyn. When leukemic cells were cultured in the presence of cyclosporin A or dexamethazone, a marked increase in apoptosis was observed as compared to cells cultured in medium alone, and this effect correlated with a great decrease in both basal activity and protein level of Lyn. The exposure of the leukemic cells to PP2 and SU6656 caused both the inhibition of the overexpressed Lyn activity and marked cell apoptosis. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target for drugs capable of inducing apoptosis in B-CLL leukemic cells.

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