BAFF and APRIL in Chronic Lymphocytic Leukemia: Clinico-Biological Correlates and Prognostic Significance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1235-1235 ◽  
Author(s):  
Gerardo Ferrer ◽  
Kate E Hodgson ◽  
Pau Abrisqueta ◽  
Aina Pons ◽  
Sonia Jansa ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocyte Count ◽  
Blood Lymphocyte ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Advanced Clinical Stage

Abstract Abstract 1235 Poster Board I-257 BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) are TNF family proteins that upregulate anti-apoptotic genes through the NF-kB pathway. Studies in vitro suggest that BAFF and APRIL protect neoplastic B cells from apoptosis in chronic lymphoproliferative disorders (CLPD) including chronic lymphocytic leukemia (CLL). Serum BAFF levels have been previously shown to be lower in CLL than in other CLPD or normal subjects. To contribute to a better understanding of their role in CLL, we analyzed BAFF and APRIL at mRNA and protein serum levels and their receptors [transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R)] by flow cytometry, in 82 patients with CLL, 36 with other CLPD and 35 age- and sex-matched controls. mRNA BAFF and APRIL levels were calculated as a the percentage of expression referred to an internal control and the receptor expression as the ratio between the mean fluorescence intensity (MFI) of the receptor antibody and the MFI of the isotype control. Patients with CLL showed significantly lower median BAFF and APRIL levels (0.63 μg/ml and 3.18 μg/ml) than those with other CLPD (1.27 μg/ml and 5.51 μg/ml) (p<0.05). Moreover, BAFF but not APRIL was lower in CLL than in healthy subjects (0.63 μg/ml vs. 0.77 μg/ml; p<0.0001). Serum BAFF levels and blood lymphocyte counts were inversely correlated. Likewise, in follicular lymphoma patients who had circulating neoplastic B cells, median BAFF levels was 0.84 μg/ml vs. 1.46 μg/ml in those without detectable neoplastic cells in blood (p<0.05). We also examined the expression of BAFF and APRIL in purified CD19+ cells from 19 CLL patients and 10 healthy controls. All CLL and normal B cells expressed BAFF and APRIL although heterogeneously. Nevertheless, BAFF and APRIL were lower in CLL than in normal B cells (median: 6.24% and 12.73% in CLL vs. 11.54% and 42.26% in controls). In CLL, mRNA BAFF expression inversely correlated with BAFF serum levels. As far as BAFF and APRIL receptors are concerned, BAFF-R was the one most highly expressed in CLL and normal B cells (MFI ratios of 167.3 and 157.2, respectively). TACI and BCMA were also expressed in all CLL cells and normal B cells (MFI ratios TACI: 1.70 and 2.41; BCMA: 9.51 and 4.72, respectively), but at a significantly lower level than BAFF-R (p<0.001). Furthermore, whereas BCMA MFI ratio was significantly higher in CLL than in normal B cells (p<0.05), no differences were observed in the expression of TACI and BAFF-R. TACI expression was heterogenous in CLL cells. BAFF-R inversely correlated with BAFF and APRIL serum levels. From a clinical standpoint, there is some indication that BAFF and APRIL serum levels as well as their expression in CLL cells may correlate with clinical and biological characteristics of the disease. No significant relationship was observed between BAFF and APRIL and IGVH mutational status, ZAP-70, CD38 or cytogenetics. However, an inverse correlation was observed between BAFF serum levels and blood lymphocyte counts as well as advanced clinical stage (p<0.05). In contrast, APRIL serum levels were only correlated with CD38 expression, the higher the expression of CD38 the higher the APRIL. Although blood lymphocyte counts and BAFF serum levels are correlated, a multivariate analysis showed that these two variables along with poor risk cytogenetics were independent predictors of progression (poor risk cytogenetics RR=11.699, p<0.05; high blood lymphocyte count RR=9.780, p<0.05 and low serum BAFF RR= 6.098, p<0.05). In summary this study confirms that BAFF and APRIL serum levels are lower in CLL than in other CLPD. In patients with CLL, BAFF serum and mRNA levels correlate with blood lymphocyte count and advanced clinical stage but not with other well known prognostic factors. Finally, although BAFF correlates with blood lymphocyte counts, our results suggest that BAFF serum levels have independent prognostic significance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344 ◽  
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3316-3325 ◽  
Author(s):  
Andrea Bürkle ◽  
Matthias Niedermeier ◽  
Annette Schmitt-Gräff ◽  
William G. Wierda ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Actin Polymerization ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Accessory Cells ◽  
Mitogen Activated Protein ◽  
B1 Cells

Abstract CXCL13 is a homeostatic chemokine for lymphocyte homing and positioning within follicles of secondary lymphoid tissues, acting through its cognate receptor, CXCR5. Moreover, the CXCR5-CXCL13 axis plays a unique role in trafficking and homing of B1 cells. Here, we report that chronic lymphocytic leukemia (CLL) B cells express high levels of functional CXCR5. CXCR5 expression levels were similar on CLL B cells and normal CD5+ B cells, and higher compared with normal CD5− B cells, follicular B-helper T cells (TFH cells), or neoplastic B cells from other B-cell neoplasias. Stimulation of CLL cells with CXCL13 induces actin polymerization, CXCR5 endocytosis, chemotaxis, and prolonged activation of p44/42 mitogen-activated protein kinases. Anti-CXCR5 antibodies, pertussis toxin, and wortmannin inhibited chemotaxis to CXCL13, demonstrating the importance of Gi proteins and PI3 kinases for CXCR5 signaling. Moreover, CLL patients had significantly higher CXCL13 serum levels than volunteers, and CXCL13 levels correlated with β2 microglobulin. We detected CXCL13 mRNA expression by nurselike cells, and high levels of CXCL13 protein in supernatants of CLL nurselike cell cultures. By immunohistochemistry, we detected CXCL13+ expression by CD68+ macrophages in situ within CLL lymph nodes. These data suggest that CXCR5 plays a role in CLL cell positioning and cognate interactions between CLL and CXCL13-secreting CD68+ accessory cells in lymphoid tissues.

CCR4:CCL17 Interaction Influences TLR-9 Mediated Cell Survival and Proliferation In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3593-3593
Author(s):  
Sonal C. Temburni ◽  
Ryon M. Andersen ◽  
Luke Janson ◽  
Xiao-Jie Yan ◽  
Barbara Sherry ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Dose Range ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Novel Therapy

Abstract Abstract 3593 Unlike other hematologic disorders, chronic lymphocytic leukemia(CLL) exhibits remarkable heterogeneity in the rates of disease progression among cases. CLL cells survive by receiving signals from the microenvironment via various receptors: B-cell antigen receptor (BCR), Toll-like receptors (TLRs) and cytokine and chemokine receptors. We previously reported that CLL clones with somatically mutated IGHVs and high (≥30%) percentage of CD38 expressing cells have the highest percentage of CCR4-expressing cells. To further explore the functional contribution of the CCR4:CCL17 axis in CLL, we studied CCL17-induced chemotactic behavior in 16 CLL cases. In transwell cultures we observed a bimodal migratory response to CCL17 at 2 doses in a dose range of 0.78– 25ng/ml, in ~60% of cases; the remaining cases showed maximal migration at a single dose (1.56 or 3.12ng/ml). A comparison of phenotypes of the migrated and non-migrated cell populations was undertaken in 10 cases, analyzing CXCR3, CXCR4, CCR4 and CCR7 that are involved in homing of cells to sites favoring growth, and CD31, CD38 and CD69, activation related molecules. The migrated cells consistently showed significantly higher percentages and densities of CD38 expression than the non-migrated cells suggesting a role for CD38 in the CCR4-mediated downstream pathway. CCR4 ligand, CCL17, is constitutively expressed in the thymus and is produced by dendritic cells, endothelial cells, keratinocytes and fibroblasts, whereas CCL22 is produced by tumor cells and the tumor microenvironment. Serum levels of both these ligands in untreated patients were quantified by ELISA. CCL17 levels ranged between 45-1, 229 pg/ml in U-CLL cases (n=23) and between 43-1, 418 pg/ml in M-CLL cases (n=30). CCL22 levels ranged between 121-5, 497 pg/ml in U-CLL cases (n=23) and 409-5, 502 pg/ml in M-CLL cases (n=30). The percentages of CCR4- expressing B cells directly correlated with percentages of T cells expressing CCR4 in individual cases, whereas they inversely correlated with both, serum levels of CCL17 (p< 0.01) and CCL22 (p< 0.05). CCL17 produced by DCs in peripheral organs may exert an accessory role in BCR- and TLR-9-mediated immune responses in B cells. We therefore tested if CCL17 supported BCR- and TLR-mediated proliferative responses in a cohort of 31 (16 U-CLL and 15M-CLL) CLL cases. CCL17 augmented BCR-mediated B-cell proliferation in 9/16 (56%) U-CLL cases, but only in 3/15 (20%) M-CLL cases. On the other hand, CCL17 showed an additive effect in promoting TLR-9-mediated cell proliferation in 13/15 (87%) M-CLL cases at a dose of 2ng/nl (approximating that detected in serum); it also augmented TLR-9 mediated B cell proliferation in 6/16 U-CLL cases but at a 5-fold or higher dose (10-25 ng/ml). In a subset of this cohort (8 cases) CCL17-induced modulation of molecules involved in the apoptotic process was studied. We found upregulation of anti-apoptotic proteins Mcl-1 and Bcl2 and down-regulation of pro-apoptotic molecules Bim, PUMA, and Bid in 5 of these cases. The pro-survival effects of CCL17 were partially abrogated by the blocking anti-CCR4 mAb (1G1). Taken together, these findings suggest that CCL17 plays a role in modulating TLR-9-mediated signaling and migration in CLL. Therefore, inhibition of CCR4:CCL17 interaction in vivo represents a novel therapy by preventing migration of CLL cells towards an environment that promotes their survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4675-4686 ◽  
Author(s):  
Marco Herling ◽  
Kaushali A. Patel ◽  
Nicole Weit ◽  
Nils Lilienthal ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Advanced Clinical Stage ◽  
Therapy Regimen ◽  
Cell Counts

Abstract Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5+ B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70+ tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.

Serum Tumor Markers in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia

1993 ◽  
Vol 8 (1) ◽  
pp. 14-20 ◽  
Author(s):  
A.N. Pavlidis ◽  
J. Kalef-Ezra ◽  
L.C. Bourantas ◽  
A. Lambrou ◽  
A. Mavridis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Markers ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Mean Values ◽  
Hodgkin's Lymphomas ◽  
Normal Controls

The levels of soluble interleukin-2 receptors (sIL-2R), beta-2 microglobulin (β-2M), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in the serum of 50 previously untreated patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) as well as in 25 age and sex-matched normal controls. Compared to normal controls, mean serum levels of sIL-2R and β-2M were significantly increased in both NHL and CLL (p < 0.001) while the increase in ESR and CRP was less marked (p < 0.01 and p < 0.05, respectively). Comparison of these tumor markers with histologic grading showed statistically significant differences only for CRP between low, intermediate and high-grade lymphomas (p < 0.001 and p < 0.05). More advanced stages exhibited higher mean values of all serum markers than early stages (p < 0.001 for sIL-2R, β-2M and ESR and p < 0.05 for CRP). An association with the presence of b-symptoms was observed only for sIL-2R (p < 0.05). In addition, sIL-2R as well as β-2M were able to predict time to progression in patients with diffuse large-cell lymphomas. We conclude that of the four tumor markers tested sIL-2R and β-2M more frequently showed increased serum levels and were associated with clinical stage and/or presence of b-symptoms. Both sIL-2R and β-2M were also found to have prognostic significance for survival.

scholarly journals The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 447-450 ◽  
Author(s):  
NE Kay ◽  
J Burton ◽  
D Wagner ◽  
DL Nelson
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Serum Levels ◽  
Mean Value ◽  
Lymphocytic Leukemia ◽  
Membrane Expression

Abstract Both membrane (p55) and soluble (p45) forms of TAC-reactive interleukin- 2 receptor (IL-2R) are expressed and/or released by activated lymphocytes or monocytes. Previous work has detected increased levels of circulating, TAC-soluble IL-2R (soluble TAC antigen) in the serum of most B-cell chronic lymphocytic leukemia (B-CLL) patients. We detected soluble TAC antigen in B-CLL patients (mean of 3,332 U/mL v 410 for controls). Serum soluble TAC antigen levels increased with stage (mean value of 1,187 U/mL for stage 0 v 2,527 for stage 2 and 5,410 for stages 3 and 4). We next attempted to determine whether the elevated serum levels of soluble TAC antigen in B-CLL patients might result from shedding or secretion of the receptor from the circulating, malignant B cells. Purified, malignant B cells from B-CLL patients were capable of producing easily detectable soluble TAC antigen after 48 hours of in vitro culture (range of 60 to 1,563 U/mL). IL-2R production by CLL B cells was dose dependent in most patients over a concentration of 10 x 10(6) to 60 x 10(6)/mL. In contrast, there was little or no detectable soluble TAC antigen when highly purified T cells from the same patients were cultured. Finally, despite elaboration of soluble IL-2R by CLL B cells, membrane expression of B-cell IL-2R was detected in only six of 11 patients. Thus, the cellular source of the elevated serum IL-2R levels is the malignant CLL B cell. Taken together these data suggest that (a) the malignant CLL B cell is “activated” in terms of release of soluble IL-2R and may serve as a tumor marker in this disease and (b) the elevated levels of circulating IL-2R may be an associated factor in the cellular immunodeficiency noted in B-CLL patients.

Characterization of Microvesicles in B-Cell Chronic Lymphocytic Leukemia (CLL): A Potential Mediator in CLL B Cell Disease Progression?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 747-747
Author(s):  
Asish K. Ghosh ◽  
Neil E. Kay
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocyte Count ◽  
Cell Communication ◽  
Annexin V ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Total Leukocyte Count ◽  
Circular Membrane

Abstract While cellular communication and interactive signaling typically relies on multiple mechanisms including secretion of various growth factors, cytokines, bioactive lipids, and adhesion molecules, we have recently focused on cell-to-cell communication that involves circular membrane vesicles designated as microvesicles (MVs). These are normal constituents of blood plasma released by leukocytes, endothelium, platelets and erythrocytes and are generated by cell activation and growth. In normal serum, the order of MV abundance is platelet-derived (80%), endothelial (10%) and leukocyte-derived (10%) but MV can also be released by malignant cells. The size varies from 0.1–1.0 μm and, MVs express antigens characteristic of the cell of origin, carry other membrane and cytoplasmic constituents and exhibit negatively charged phospholipids (phosphatidylserine) detectable by Annexin V binding. To begin to characterize MV and their potential for communication in CLL, we isolated and characterized MVs from the plasma of chronic lymphocytic leukemia B-cell (CLL B) patients (Rai 0-IV). After isolation from platelet-free plasma, MVs were characterized by flow cytometry for forward and side scatter using 1μm fluorescent beads and stained with Annexin V. Our results suggest that MVs are heterogeneous in size with the majority of MVs within 1μm. Transmission electron microscopy confirmed the size heterogeneity of MVs and exhibited the morphology of the membrane-bound vesicles after phosphotungstic acid staining onto parlodium-coated 300 mesh copper grids. Flow cytometric analysis further demonstrated the presence of CD61 (platelet/megakaryocyte marker), CD19, CD5, CD52, and CD20 on the surface of MV, albeit in differential amounts depending on the stage of the disease and the total leukocyte count. For example, in Rai stage IV (n= 5), we found lesser numbers of MV carrying platelet-derived marker CD61 and more CD19 (41–79%), and CD5 compared to normal MV; 1–5% MV from healthy controls expressed CD19 while Rai stage 4 patients MV expressed CD19 from 41–79%. These results suggest that a significant number of MVs are generated from the leukemic B-lymphocytes in more advanced Rai stage. However, we also found that patients with a higher blood lymphocyte count but lower Rai-stage (Rai I/II) contain moderate levels of CD19-bearing MVs (13–43%). Importantly, presence of MVs carrying CD52/CD20 in the blood of CLL patients may undermine the therapeutic effectiveness of alemtuzumab and rituximab. To this end, we observed that MVs could be incorporated into the CLL B cells as evident from the expression of the platelet antigen CD61 on CLL B cell surfaces after co-culture of CD61-bearing MVs with CLL B cells. Global proteomic analysis of MVs isolated from an advanced stage (Rai IV) CLL B patient detected the presence of about 700 proteins that normally reside in the nucleus, cytoplasm or membrane. In summary, we have isolated and characterized plasma MV from CLL B patients and found them to be more likely generated from CLL B cells in relation to disease stage or total lymphocyte count. These MVs contain a multitude of proteins and are able to integrate into bystander CLL B cells. We also found that these MVs carry a large set of proteins, which could potentially not only modulate cell-cell communication but also interrupt monoclonal antibody directed therapy. Further studies are underway to dissect their roles in CLL B malignancy.

scholarly journals The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 447-450 ◽  
Author(s):  
NE Kay ◽  
J Burton ◽  
D Wagner ◽  
DL Nelson
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Serum Levels ◽  
Mean Value ◽  
Lymphocytic Leukemia ◽  
Membrane Expression

Both membrane (p55) and soluble (p45) forms of TAC-reactive interleukin- 2 receptor (IL-2R) are expressed and/or released by activated lymphocytes or monocytes. Previous work has detected increased levels of circulating, TAC-soluble IL-2R (soluble TAC antigen) in the serum of most B-cell chronic lymphocytic leukemia (B-CLL) patients. We detected soluble TAC antigen in B-CLL patients (mean of 3,332 U/mL v 410 for controls). Serum soluble TAC antigen levels increased with stage (mean value of 1,187 U/mL for stage 0 v 2,527 for stage 2 and 5,410 for stages 3 and 4). We next attempted to determine whether the elevated serum levels of soluble TAC antigen in B-CLL patients might result from shedding or secretion of the receptor from the circulating, malignant B cells. Purified, malignant B cells from B-CLL patients were capable of producing easily detectable soluble TAC antigen after 48 hours of in vitro culture (range of 60 to 1,563 U/mL). IL-2R production by CLL B cells was dose dependent in most patients over a concentration of 10 x 10(6) to 60 x 10(6)/mL. In contrast, there was little or no detectable soluble TAC antigen when highly purified T cells from the same patients were cultured. Finally, despite elaboration of soluble IL-2R by CLL B cells, membrane expression of B-cell IL-2R was detected in only six of 11 patients. Thus, the cellular source of the elevated serum IL-2R levels is the malignant CLL B cell. Taken together these data suggest that (a) the malignant CLL B cell is “activated” in terms of release of soluble IL-2R and may serve as a tumor marker in this disease and (b) the elevated levels of circulating IL-2R may be an associated factor in the cellular immunodeficiency noted in B-CLL patients.

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