scholarly journals Immunoglobulin phenotype on B cells correlates with clinical stage of chronic lymphocytic leukemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 256-263
Author(s):  
FS Ligler ◽  
JR Kettman ◽  
RG Smith ◽  
EP Frenkel
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Light Chain Type ◽  
Immature B Cells ◽  
Advanced Stages ◽  
Ig Heavy Chain ◽  
Chain Type

The present study examines the relative amounts of surface immunoglobulin (Ig) on lymphocytes obtained from 64 patients with chronic lymphocytic leukemia (CLL) and correlates these findings with the clinical stage of disease. Since the maturing B cell first expresses surface IgM, followed by IgD, and subsequently by IgG, IgA, or IgE, the surface Ig phenotype can be used as a marker of differentiation. Surface Ig was analyzed using the fluorescence- activated cell sorter under carefully controlled conditions. The cells from all patients with CLL were monoclonal with respect to light chain type. Those patients with IgM as the brightest heavy chain class (suggesting relatively immature B cells) had clinically advanced stages of CLL, whereas those with a predominance of IgG (suggesting more mature cells) have a lesser stage of CLL. Thus, the predominant Ig heavy chain class appears to correlate with clinical stage of CLL and provides a clue to the potential aggressiveness of the tumor.

scholarly journals Immunoglobulin phenotype on B cells correlates with clinical stage of chronic lymphocytic leukemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 256-263 ◽  
Author(s):  
FS Ligler ◽  
JR Kettman ◽  
RG Smith ◽  
EP Frenkel
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Light Chain Type ◽  
Immature B Cells ◽  
Advanced Stages ◽  
Ig Heavy Chain ◽  
Chain Type

Abstract The present study examines the relative amounts of surface immunoglobulin (Ig) on lymphocytes obtained from 64 patients with chronic lymphocytic leukemia (CLL) and correlates these findings with the clinical stage of disease. Since the maturing B cell first expresses surface IgM, followed by IgD, and subsequently by IgG, IgA, or IgE, the surface Ig phenotype can be used as a marker of differentiation. Surface Ig was analyzed using the fluorescence- activated cell sorter under carefully controlled conditions. The cells from all patients with CLL were monoclonal with respect to light chain type. Those patients with IgM as the brightest heavy chain class (suggesting relatively immature B cells) had clinically advanced stages of CLL, whereas those with a predominance of IgG (suggesting more mature cells) have a lesser stage of CLL. Thus, the predominant Ig heavy chain class appears to correlate with clinical stage of CLL and provides a clue to the potential aggressiveness of the tumor.

scholarly journals Use of IGHV3–21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post–germinal center leukemogenic selection

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5101-5108 ◽  
Author(s):  
Emanuela M. Ghia ◽  
Sonia Jain ◽  
George F. Widhopf ◽  
Laura Z. Rassenti ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germinal Center ◽  
Variable Region ◽  
Initial Therapy ◽  
Lymphocytic Leukemia ◽  
Region Gene ◽  
High Risk Disease ◽  
Research Consortium ◽  
Ig Heavy Chain

Abstract We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

scholarly journals IgE synthesis by chronic lymphocytic leukemia cells.

1989 ◽  
Vol 170 (5) ◽  
pp. 1775-1780 ◽  
Author(s):  
M Sarfati ◽  
H Luo ◽  
G Delespesse
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Fluorescence Staining ◽  
Immunological Parameters ◽  
Potent Inducer ◽  
Human B Cells ◽  
Ige Synthesis ◽  
Cd23 Expression ◽  
Chain Type

The present results indicate that B cells isolated from chronic lymphocytic leukemia (B-CLL) from 11 of 14 patients are capable of specifically producing IgE upon costimulation with IL-4 and hydrocortisone (HC). IgE is detected by intracytoplasmic fluorescence staining and by RIA. Clinical, hematological, and immunological parameters (including Rai stage, WBC, Lc, sIg kappa/lambda, CD5, and CD23 expression) cannot distinguish the IgE responder from the nonresponder patients. IL-4 alone is a potent inducer of human IgE synthesis by normal PBMC and we show here that its effect is strikingly enhanced by HC. The IgE produced by B-CLLs are monoclonal since they display the same L chain type as the freshly isolated CD5+ B-CLLs. We, therefore, conclude that the combination of IL-4 and HC can abrogate the maturation arrest of CD5+ B-CLLs by inducing their differentiation into IgE-producing cells. The present data provide a unique model to study the isotype switching to IgE and the regulation of human IgE synthesis by monoclonal human B cells.

scholarly journals High incidence of serum monoclonal Igs detected by a sensitive immunoblotting technique in B-cell chronic lymphocytic leukemia

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1216-1219 ◽  
Author(s):  
A Beaume ◽  
A Brizard ◽  
B Dreyfus ◽  
JL Preud'homme
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Light Chain ◽  
Early Stage ◽  
Lymphocytic Leukemia ◽  
Cell Functions ◽  
Lymphocyte Surface ◽  
Light Chain Type ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Chain Type

In a prospective study in 65 untreated patients with early-stage B-cell chronic lymphocytic leukemia (B-CLL), serum monoclonal Igs (moIg) were evidenced in 80% of cases by a sensitive immunoblotting procedure. These low-abundance moIg were generally undetectable by immunoelectrophoresis and individual sera often contained several of them. Their kappa/lambda ratio was close to 1 instead of 2.8 for the lymphocyte surface Igs. A monoclonal IgM of the same light-chain type as the lymphocyte surface IgM was found in 26 sera only. The distribution of the heavy-chain classes and subclasses and light-chain types of the serum moIg was similar to those observed in aging (with a higher incidence and no correlation with age in B-CLL) and conditions with defective T-cell functions. Using a specific filter affinity- transfer assay, rheumatoid factors were detected in 58.5% of sera. However, homogeneous anti-IgG antibodies corresponding to a monoclonal IgM of the same light-chain type as the surface IgM were found in 10 patients only. These data suggest that the majority of discrete serum moIg in B-CLL are not secretion products of the leukemic clones and likely result from the immunodeficiency state inherent in the disease.

Study of VH3-21 in a Large Cohort of Chronic Lymphocytic Leukemia Patients Reveals Evidence for Antigen Selection and Confirms Its Predictive Value for Early Disease Progression.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2774-2774
Author(s):  
Emanuela M. Ghia ◽  
Laura Z. Rassenti ◽  
George F. Widhopf ◽  
Donna S. Neuberg ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
United States ◽  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Heavy Chain ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
Early Disease ◽  
Ig Heavy Chain

Abstract The use frequency of the immunoglobulin (Ig) heavy chain variable region gene (VH) 3–21 in chronic lymphocytic leukemia (CLL) varies among studies on various cohorts of European patients, ranging from 0.9%–10%. Such variation could be due to geographic/population differences and/or sample-size limitations. We examined a large cohort (N=2,190) of CLL patients evaluated in the United States by the CLL Research Consortium (CRC) and found 56 (2.6%) used IgVH3-21. Thirty-five of the 56 cases (63%) expressed Ig light chains, whereas only 821 (38%) of the 2,134 cases that used IgVH other than IgVH3-21 used light chains, a difference that was highly significant (P < 0.001). Cases that used IgVH3-21 and light chains had significantly fewer amino acid residues in Ig heavy chain third complementarity determining region (CDR3) (m = 11.5 ± 5.3, S.D.) than did VH3-21 cases with light chains (m = 18.4 ± 4.8) (P<0.001). Twenty-eight of the 56 cases (50%) used unmutated IgVH3-21, defined as having >98% homology to germline VH3-21. Twenty (43%) or 18 (38%) of the 47 cases examined by flow cytometry expressed ZAP-70 or high-level CD38, respectively. Although there was frequent concordant expression of ZAP-70 and/or CD38 with unmutated IgVH3-21, such associations were not absolute, as had been noted for CLL cases that did not use IgVH3-21. Thirty-two percent (18/56) of the cases had a previously described common amino-acid motif (ARDANGMDV) in the otherwise highly variable Ig heavy-chain CDR3. Seventeen (94%) of such cases used light chains typically encoded by V3-21/J3. In addition, we identified a novel amino-acid consensus motif (DPSFYSSSWTLFDY) in the Ig heavy chain CDR3 for 3 of the 56 cases (5.4%). We examined the time from diagnosis to initiation of therapy as per established NCI-Working Group guidelines in 40 patients for whom complete clinical data were available. With a median follow-up of 4.2 years from the date of diagnosis, 25 of the 40 patients had received therapy at the time of this analysis. The median time to treatment (TTT) for all 40 patients was 3.5 years, which was significantly shorter than the median TTT of 6.6 years noted for a previously-described CRC cohort of 307 patients that were not selected for use of IgVH3-21 (NEJM2004; 351: 893–901) (P<0.001). The median TTT of 19 patients that used unmutated IgVH3-21 in this subset (3.0 years) appeared shorter than that noted for the 21 patients that had mutated IgVH3-21 (5.4 years), but this difference did not reach statistical significance. We conclude that a small proportion of patients studied in the United States by the CRC use IgVH3-21, which encodes Ig heavy chains that frequently have canonical motifs in the CDR3 and that typically are paired with certain Ig light chains, providing strong evidence for Ig selection by antigen(s). Finally, patients with IgVH3-21-expressing CLL have a higher risk for early disease progression than do patients with CLL not selected for use of IgVH3-21.

Expression of Ig-β (CD79b) by chronic lymphocytic leukemia B cells that lack immunoglobulin heavy-chain allelic exclusion

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2725-2727 ◽  
Author(s):  
Laura Z. Rassenti ◽  
Thomas J. Kipps
Keyword(s):  
Signal Transduction ◽  
Monoclonal Antibodies ◽  
Genetic Polymorphism ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Leukemia Cell ◽  
Immunoglobulin Heavy Chain ◽  
Lymphocytic Leukemia ◽  
Allelic Exclusion

Abstract Because immunoglobulin (Ig)-β (CD79b) is required for immunoglobulin allelic exclusion, we examined the CD79b expressed by four chronic lymphocytic leukemia (CLL) samples that expressed more than one immunoglobulin heavy-chain allele and five samples that had normal immunoglobulin heavy-chain allelic exclusion. All leukemia cell samples stained poorly with monoclonal antibodies specific for extracellular epitopes of CD79b. However, all samples expressed functional CD79b genes, regardless of whether they did or did not express more than one immunoglobulin heavy-chain allele. We identified variant CD79b genes that had conservative base substitutions restricted to regions encoding the extracellular immunoglobulin-like domain of CD79b. However, these variants were not restricted to samples lacking immunoglobulin heavy-chain allelic exclusion and most likely reflect genetic polymorphism. Collectively, these data indicate that the unusual expression of more than one immunoglobulin heavy allele by CLL B cells is not associated with structural, nonconservative mutations in the signal-transduction domains of CD79b.

scholarly journals Lack of Allelic Exclusion in B Cell Chronic Lymphocytic Leukemia

1997 ◽  
Vol 185 (8) ◽  
pp. 1435-1446 ◽  
Author(s):  
Laura Z. Rassenti ◽  
Thomas J. Kipps
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Protein A ◽  
Lymphocytic Leukemia ◽  
Allelic Exclusion ◽  
Staphylococcal Protein A ◽  
Vh Genes ◽  
Ig Heavy Chain ◽  
Cell Chronic Lymphocytic Leukemia

We determined the immunoglobulin (Ig) VH subgroup expressed by the leukemia cells of 108 patients with B cell chronic lymphocytic leukemia (CLL). Surprisingly, we found that six samples (5%) each expressed Ig of more than one VH subgroup. Southern blot analysis demonstrated that these samples each had rearrangements involving both Ig heavy chain alleles. Nucleic acid sequence analyses of the Ig cDNA revealed each to express two functional Ig VH genes: VH3-33 and VH4-39; VH3-7 and VH4-39; VH3-23 and VH4-61; VH2-70 and VH3-30.3; or VH3-30 and VH4-b (DP67). One sample expressed three Ig VH genes: VH2-70, VH3-7, and VH4-59. Despite having more than one Ig heavy chain transcript, each sample was found to express only one functional Ig light chain. From the primary sequence, we deduced that the Ig of some of these CLL samples should react with Lc1, a monoclonal antibody (mAb) reactive with a supratypic cross-reactive idiotype present on Ig encoded by a subgroup of Ig VH4 genes (namely, VH4-39, VH4-b [DP-67], VH4-59, or VH4-61), and B6, an mAb that reacts with Ig encoded by certain Ig VH3 genes (namely, VH3-23, VH3-30, or VH3-30.3), and/or modified staphylococcal protein A (SpA), a 45-kilodalton bacterial “superantigen” that reacts with most Ig of the VH3 subgroup. Flow cytometric analyses revealed that such samples did in fact react with Lc1 and B6 and/or SpA, but not with control mAbs of irrelevant specificity. This study demonstrates that a subset of CLL patients have leukemic B cells that express more than one functional Ig heavy chain.

ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2036-2041 ◽  
Author(s):  
Liguang Chen ◽  
John Apgar ◽  
Lang Huynh ◽  
Frank Dicker ◽  
Teresa Giago-McGahan ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Variable Region ◽  
Adenovirus Vector ◽  
Lymphocytic Leukemia ◽  
Clinical Behavior ◽  
Heavy Chain Variable Region ◽  
Variable Region Genes ◽  
Aggressive Clinical Behavior

Abstract Chronic lymphocytic leukemia (CLL) B cells that express unmutated immunoglobulin heavy-chain variable region genes (IgVH) generally express ZAP-70, in contrast to normal B cells or most CLL cases with mutated IgVH. Following IgM ligation, ZAP-70+ CLL cells had significantly higher levels of phosphorylated p72Syk, BLNK, and phospholipase-Cγ (PLCγ) and had greater[Ca2+]i flux than did ZAP-70–negative CLL cases, including unusual ZAP-70–negative cases with unmutated IgVH. IgM ligation of ZAP-70–negative CLL B cells infected with an adenovirus vector encoding ZAP-70 induced significantly greater levels of phosphorylated p72Syk, BLNK, and PLCγ and had greater[Ca2+]i flux than did similarly stimulated, noninfected CLL cells or CLL cells infected with a control adenovirus vector. We conclude that expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgVH.

Restricted Pairing of Immunoglobulin Heavy and Light Chains Expressed by Chronic Lymphocytic Leukemia B Cells Is Predicated on the Heavy Chain CDR3.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2094-2094
Author(s):  
George F. Widhopf ◽  
Craig J. Goldberg ◽  
Traci L. Toy ◽  
Laura Z. Rassenti ◽  
Thomas J. Kipps
Keyword(s):  
Amino Acid ◽  
B Cells ◽  
Heavy Chain ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
Sequence Motif ◽  
Amino Acid Motif ◽  
Heavy Chains ◽  
Vh Genes ◽  
Ig Heavy Chain

Abstract Analysis of the immunoglobulin (Ig) heavy chains expressed by the leukemic B cells of patients with chronic lymphocytic leukemia (CLL) has demonstrated that expression of Ig variable heavy chain (VH) genes in CLL is not random. Certain VH genes are more frequently expressed in CLL than in the normal adult B cell repertoire, and some, such as the 51p1 allele of VH1-69, also use of certain diversity (D) and junctional (JH) gene segments that encode third complementarity determining regions (CDR3) with conserved molecular structures. We identified 15 CLL cases among 1,220 examined that express nearly identical Ig heavy and light chains, encoded by 51p1/D3-16/JH3 and VKA27, respectively (Blood, 104:2499, 2004). The highly restricted and virtually identical structure of these B cell receptors strongly suggests selection for Ig in CLL that have a particular binding activity. However, little information is currently available about the light chains expressed by CLL B cells that have 51p1-encoded Ig heavy chains that use other D and JH segments encoding CDR3 that also are repeatedly observed in this disease. We analyzed the VL genes used by 235 CLL cases found to express 51p1-encoded Ig heavy chains among 1,605 CLL patients examined. First, we find restricted light chain isotype expression, as 72% of samples express kappa and 28% express lambda light chains, compared to 65% kappa and 35% lambda within the cohort of all 1,605 CRC CLL samples, and about 60% kappa and 40% lambda expression in normal blood B cells. Nucleotide sequence analysis of the Ig light chain V gene used by these 235 cases revealed that each had greater than 98% homology to an identified germline VK or Vl gene. Additionally, we identified non-stochastic pairing of particular VK and Vl genes with 51p1-encoded heavy chains that have highly-conserved CDR3. Twenty of the 235 cases (8.5%) were found to have Ig light chains encoded by VKO2. Seventeen (85%) of such cases had 51p1-encoded Ig heavy chains that used D2-2 and JH6, 15 of which had nearly identical CDR3 using the amino acid motif DIVVVPAAI. The VKO2-encoded light chains paired with these Ig heavy chains all had nearly identical CDR3 with the amino acid sequence motif QQSYSTPRT. Similarly, seven of the 235 cases (3%) were found to have Ig light chains encoded by Vl3-9. Six (86%) of such cases had 51p1-encoded Ig heavy chains that used D3-3 and JH6, and all had highly conserved heavy chain CDR3 with the amino acid motif YDFWSGYYPNYYYYGMDV. The Vl3-9-encoded light chains paired with these Ig heavy chains all had nearly identical CDR3 with the amino acid sequence motif QVWDSSTXV. Finally, we identified seven additional samples that express a heavy chain using D3-16 and JH3 that have nearly identical CDR3 amino acid sequences GGGYDYIWGSYRPNDAFDI, and also express light chains encoded by VKA27. These seven samples combined with the previous 15 represent all of the 51p1-encoded heavy chains that utilize D3-16 and JH3, as well as 52% (22 of 42) of all 51p1-encoded CLL samples that express VKA27-encoded light chains. These studies reveal for the first time that CLL cases using the same unmutated Ig heavy chain have non-stochastic pairing with disparate Ig light chains that is predicated upon the Ig heavy chain CDR3 structure. Because the CDR3 typically forms a major part of antibody binding site(s) for antigen, these data provide compelling evidence for antigen selection of the antibodies expressed in CLL.

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.

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