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

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3584-3592 ◽  
Author(s):  
Sarah J. Richardson ◽  
Christine Matthews ◽  
Mark A. Catherwood ◽  
H. Denis Alexander ◽  
B. Sean Carey ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Actin Polymerization ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Cellular Migration ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

Molecular markers like IgVH 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-α, 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.

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1063-1070 ◽  
Author(s):  
Mohammad-Reza Rezvany ◽  
Mahmood Jeddi-Tehrani ◽  
Hans Wigzell ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cd8 T Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Abstract T-cell receptor–B-variable (TCR-BV) gene usage and the CDR3 size distribution pattern were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) in patients with B-cell chronic lymphocytic leukemia (B-CLL) to assess the T-cell repertoire. The use of TCR-BV families in CD4 and CD8 T cells stimulated with autologous activated leukemic cells was compared with that of freshly obtained blood T cells. Overexpression of individual TCR-BV families was found in freshly isolated CD4 and CD8 T cells. Polyclonal, oligoclonal, and monoclonal TCR-CDR3 patterns were seen within such overexpressed native CD4 and CD8 TCR-BV families. In nonoverexpressed TCR-BV families, monoclonal and oligoclonal populations were noted only within the CD8 subset. After in vitro stimulation of T cells with autologous leukemic B cells, analyses of the CDR3 length patterns showed that in expanded TCR-BV populations, polyclonal patterns frequently shifted toward a monoclonal/oligoclonal profile, whereas largely monoclonal patterns in native overexpressed TCR-BV subsets remained monoclonal. Seventy-five percent of CD8 expansions found in freshly obtained CD8 T cells further expanded on in vitro stimulation with autologous leukemic B cells. This suggests a memory status of such cells. In contrast, the unusually high frequency of CD4 T-cell expansions found in freshly isolated peripheral blood cells did not correlate positively to in vitro stimulation as only 1 of 9 expansions continued to expand. Our data suggest that leukemia cell–specific memory CD4 and CD8 T cells are present in vivo of patients with CLL and that several leukemia cell–associated antigens/epitopes are recognized by the patients' immune system, indicating that whole leukemia cells might be of preference for vaccine development.

Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2777-2783 ◽  
Author(s):  
Luisa Granziero ◽  
Paolo Ghia ◽  
Paola Circosta ◽  
Daniela Gottardi ◽  
Giuliana Strola ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Survivin Expression ◽  
Lymphocytic Leukemia ◽  
Cd40 Stimulation ◽  
Cell Chronic Lymphocytic Leukemia

Abstract In B-cell chronic lymphocytic leukemia (B-CLL), defective apoptosis causes the accumulation of mature CD5+ B cells in lymphoid organs, bone marrow (BM), and peripheral blood (PB). These cells are the progeny of a proliferating pool that feeds the accumulating compartment. The authors sought to determine which molecular mechanisms govern the proliferating pool, how they relate to apoptosis, and what the role is of the microenvironment. To begin to resolve these problems, the expression and modulation of the family of inhibitor of apoptosis proteins (IAPs) were investigated, with consideration given to the possibility that physiological stimuli, such as CD40 ligand (CD40L), available to B cells in the microenvironment, might modulate IAP expression. The in vitro data on mononuclear cells from PB or BM of 30 patients demonstrate that B-CLL cells on CD40 stimulation express Survivin and that Survivin is the only IAP whose expression is induced by CD40L. Through immunohistochemistry, in vivo Survivin expression in lymph node (LN) and BM biopsies was evaluated. In reactive LN, Survivin was detected only in highly proliferating germinal center cells. In LN from patients with B-CLL, Survivin was detected only in pseudofollicles. Pseudofollicle Survivin+ cells were actively proliferating and, in contrast to Survivin+ B cells found in normal GC, were Bcl-2+. In B-CLL BM biopsies, CD5+, Survivin+ cells were observed in clusters interspersed with T cells. These findings establish that Survivin controls the B-CLL proliferative pool interfacing apoptosis and that its expression may be modulated by microenvironmental stimuli.

Elevated Levels of IL-17, MIP-1 β, MIG and ITAC in B-Cell Chronic Lymphocytic Leukemia: Correlation with Prognostic Markers.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2788-2788
Author(s):  
Xiao J. Yan ◽  
Michael Centola ◽  
Igor Dozmorov ◽  
Rajendra N. Damle ◽  
Steven L. Allen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Stromal Cells ◽  
Lymphocytic Leukemia ◽  
Serum Cytokines ◽  
Cd38 Expression ◽  
Cytokines And Chemokines ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of mature B cells. The growth and accumulation of B-CLL cells requires survival and migratory signals from endogenously produced cytokines and chemokines, many of which are supplied by stromal cells. In this comparative study we analyzed the expression, as a function of B-CLL disease, of a set of inflammatory and immune cytokines and chemokines known to regulate the growth, survival and/or trafficking of B cells. Serum cytokines were measured in 87 B-CLL patients and in 32 healthy subjects using a combination of multiplex cytokine bead and protein array technologies. A subset of cytokines and chemokines were found to be significantly elevated in serum from B-CLL patients as compared to healthy age-matched controls: IL-17 (p<0.01), MIP-1β (p<0.001), MIP-1α (p<0.01), IL-6 (p<0.05), IL-8 (p<0.001), IL-10 (p<0.001), IL-12 (p<0.05), MIG (p<0.01), and ITAC (p<0.001). Serum levels of IL-1β, IL-1α, IL-2, IL-4, IL-5, IL-12, IL-13, IL-15, TNFα, IFNγ, IFNα, GM-CSF, Eotaxin, and MCP-1 were not significantly different in B-CLL patients as compared to healthy age-matched controls. Previous studies have reported elevated levels of IL-6, IL-8, IL-10, and MIG in B-CLL, and these molecules may contribute anti-apoptotic and growth-promoting signals that allow the expansion of B-CLL cells. IL-17 is known to promote angiogenesis and induce stromal cell expression of cytokines and chemokines that support B-CLL survival, suggesting potential mechanisms whereby this cytokine may impact on B-CLL biology. MIG and ITAC are ligands for CXCR3, a chemokine receptor expressed on B-CLL cells. These chemokines positively affect the responsiveness of pDC to the homing chemokine, SDF-1, raising the possibility that their elevation in B-CLL may lead to increased responsiveness of B-CLL cells to SDF-1, a stromal factor that enhances their survival. MIP-1α and MIP-1β are inflammatory chemokines that regulate cell recruitment and activation. Interestingly, MIP-1α and MIP-1β trigger stromal cells to produce RANKL, which has recently been suggested to contribute to B-CLL pathogenesis by triggering production of IL-8. B-CLL patients divide into populations that present with (a) stable disease and favorable prognostics including mutated VH and low CD38 expression, and (b) progressive disease with poor prognostics including unmutated VH and high CD38. When serum cytokines were analyzed as a function of select prognostic indicators discrete differences were observed. IL-8 levels correlated with mutated VH, IL-17 and IL-6 levels correlated with unmutated VH, and MIG, IP-10 and ITAC levels correlated with high CD38 expression. MIP-1α and MIP-1β levels differed significantly from controls irrespective of mutational status or CD38 expression. The correlation of IL-17, which in addition to its stromal activating properties is known to promote angiogenesis, with unmutated VH suggests a potential role for this cytokine in mediating the increased angiogenic phenotype that has been observed in poor prognosis CLL.

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

scholarly journals Normal cellular counterparts of B cell chronic lymphocytic leukemia

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 418-427
Author(s):  
AS Freedman ◽  
AW Boyd ◽  
FR Bieber ◽  
J Daley ◽  
K Rosen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
B Cell Activation ◽  
Activation Antigens ◽  
Cell Chronic Lymphocytic Leukemia

In an attempt to compare B cell chronic lymphocytic leukemia (B-CLL) with its normal cellular counterpart, the cell surface phenotype of 100 cases of B-CLL was determined by using a panel of monoclonal antibodies (MoAbs) directed against B cell-restricted and -associated antigens. The majority of B-CLL cells expressed Ia, B4 (CD19), B1 (CD20), B2 (CD21), surface immunoglobulin (sIg), and T1 (CD5) but lacked C3b (CD35) receptors. In contrast, the overwhelming majority of small unstimulated B cells expressed Ia, B4, B1, B2, sIg, and C3b receptors but lacked detectable T1. Small numbers of weakly sIg+ cells could be identified in peripheral blood and tonsil that coexpressed the B1 and T1 antigens. Approximately 16% of fetal splenocytes coexpressed B1, T1, weak sIg, B2, and Ia but lacked C3b receptors and therefore closely resembled most B-CLL cells. With the phenotypic differences between the majority of small unstimulated B cells and B-CLL cells, we examined normal in vitro activated B cells and B-CLL cells for the expression of B cell-restricted and -associated activation antigens. Of 20 cases examined, virtually all expressed B5, and approximately 50% of the cases expressed interleukin-2 receptors (IL-2R) and Blast-1. Normal B cells were activated with either anti-Ig or 12–0-tetradecanoylphorbol- beta-acetate (TPA) and then were examined for coexpression of B1, T1, and the B cell activation antigens B5 and IL-2R. Only cells activated with TPA coexpressed B1 and T1 as well as B5 and IL-2R. B cells activated with either anti-Ig or TPA proliferated in the presence of IL- 2, whereas B-CLL cells did not, although they all expressed the identical 60-kilodalton proteins by immunoprecipitation. These studies are consistent with the notion that B-CLL resembles several minor subpopulations of normal B cells including a population of B cells that are activated in vitro directly through the protein kinase C pathway.

A Monoclonal Antibody Specifically Targeting CD44 Inhibits B-Cell Chronic Lymphocytic Leukemia Cell Survival In Vitro and In Vivo

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 927-927
Author(s):  
Suping Zhang ◽  
Christina C.N. Wu ◽  
Jessie-Farah Fecteau ◽  
Bing Cui ◽  
Rongrong Wu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Survival ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Equity Ownership ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 927 B-cell chronic lymphocytic leukemia (CLL) with a highly variable clinical course is characterized by the clonal expansion of CD5+ B cells in blood, secondary lymphoid tissues, and marrow. Survival of CLL cells are supported by cells within the tissue microenvironment and by signals from the extracellular matrix, which in part are mediated via interactions with CD44, a surface glycoprotein that is expressed at high levels by CLL B cells. While monoclonal antibody (mAb) therapy targeting CD20 has improved the survival of patients with CLL, a large number of CLL patients do not achieve durable responses or become refractory altogether to therapy with anti-CD20 mAb. In this study we evaluated the cytotoxic activity against CLL cells of a newly developed, humanized anti-CD44 mAb (RO5429083, Roche). We found that sub-microgram concentrations of this anti-CD44 mAb were directly cytotoxic for CLL cells of different patients (n = 32), but had little or no effect on the viability of lymphocytes isolated from the blood of healthy donors (n = 4). The levels of cytotoxicity induced by this anti-CD44 mAb were significantly associated with the levels of CD44 expressed by each of the CLL samples (Spearman R-0.5785, p<0.001). Furthermore, survival and downstream signaling events of CLL cells induced by hyaluronic acid (HA), the principal ligand of CD44, were inhibited by this CD44 mAb. Of note, this CD44 mAb also was equally cytotoxic for CLL cells co-cultured with mesenchymal stromal cells (MSC), which otherwise can support CLL-cell survival in vitro. We also examined whether this anti-CD44 mAb could induce clearance of human CLL cells engrafted into immune deficient RAG-2−/−/γc−/− mice. Treatment of such xenografted animals with as little as 1 mg/kg of this mAb resulted in the complete clearance of engrafted CLL cells, an effect not observed in control treated animals. Based on these pre-clinical studies, we consider this anti-CD44 mAb has high potential for providing effective treatment for patients with this disease. Disclosures: Weigland: Roche Diagnostics GmbH: Employment. Carson:Wintherix: Equity Ownership. Kipps:Gilead Sciences: Consultancy, Research Funding; GSK: Research Funding; Genentech: Research Funding; Abbott Industries: Research Funding; Celgene: Consultancy, Research Funding; Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

scholarly journals Normal cellular counterparts of B cell chronic lymphocytic leukemia

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 418-427 ◽  
Author(s):  
AS Freedman ◽  
AW Boyd ◽  
FR Bieber ◽  
J Daley ◽  
K Rosen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
B Cell Activation ◽  
Activation Antigens ◽  
Cell Chronic Lymphocytic Leukemia

Abstract In an attempt to compare B cell chronic lymphocytic leukemia (B-CLL) with its normal cellular counterpart, the cell surface phenotype of 100 cases of B-CLL was determined by using a panel of monoclonal antibodies (MoAbs) directed against B cell-restricted and -associated antigens. The majority of B-CLL cells expressed Ia, B4 (CD19), B1 (CD20), B2 (CD21), surface immunoglobulin (sIg), and T1 (CD5) but lacked C3b (CD35) receptors. In contrast, the overwhelming majority of small unstimulated B cells expressed Ia, B4, B1, B2, sIg, and C3b receptors but lacked detectable T1. Small numbers of weakly sIg+ cells could be identified in peripheral blood and tonsil that coexpressed the B1 and T1 antigens. Approximately 16% of fetal splenocytes coexpressed B1, T1, weak sIg, B2, and Ia but lacked C3b receptors and therefore closely resembled most B-CLL cells. With the phenotypic differences between the majority of small unstimulated B cells and B-CLL cells, we examined normal in vitro activated B cells and B-CLL cells for the expression of B cell-restricted and -associated activation antigens. Of 20 cases examined, virtually all expressed B5, and approximately 50% of the cases expressed interleukin-2 receptors (IL-2R) and Blast-1. Normal B cells were activated with either anti-Ig or 12–0-tetradecanoylphorbol- beta-acetate (TPA) and then were examined for coexpression of B1, T1, and the B cell activation antigens B5 and IL-2R. Only cells activated with TPA coexpressed B1 and T1 as well as B5 and IL-2R. B cells activated with either anti-Ig or TPA proliferated in the presence of IL- 2, whereas B-CLL cells did not, although they all expressed the identical 60-kilodalton proteins by immunoprecipitation. These studies are consistent with the notion that B-CLL resembles several minor subpopulations of normal B cells including a population of B cells that are activated in vitro directly through the protein kinase C pathway.

scholarly journals Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

2001 ◽  
Vol 194 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Andreas Rosenwald ◽  
Ash A. Alizadeh ◽  
George Widhopf ◽  
Richard Simon ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Gene Expression Signature ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Human Leukemia ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

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