Inversely Association of the Aiolos Transcription Factor with Clinical Progression in Chronic Lymphocytic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2069-2069
Author(s):  
Holger Nückel ◽  
Ulrich H Frey ◽  
Ludger Sellmann ◽  
Crista H Collins ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Pcr Analysis ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Cd38 Expression ◽  
Important Regulator

Abstract Introduction: Aiolos encode a hemopoietic-specific zinc-finger transcription factor that is an important regulator of lymphocyte differentiation and plays a critical role in regulating B-cell development. RT-PCR analysis of the Aiolos gene expression revealed 16 Aiolos splicing variants, which have been named according to the exons missing from the full-length isoform. Recent data suggest that over 80% of expressed Aiolos in normal as well as in malignant B-cells is of the hAio1 type. Therefore, we investigated Aiolos mRNA expression (hAio1 type) in a large cohort with 155 patients along with the most commonly used biological markers in order to assess its role in risk prediction in B-CLL. Methods and Results: The total amount of Aiolos transcripts in B-cells of 155 CLL patients using normal peripheral blood mononuclear cells represented a continuum ranging from 2.5- to 37-fold upregulation compared to that of normal B-cells, with a median of 20- fold upregulation. Moreover, Aiolos expression in B-CLL was significantly upregulated compared to cells of AML (113-fold; p<0.0001), ALL (14-fold; p=0.0024), CML (154- fold; p<0.0001), multiple myeloma (38-fold; p=0.0018) or NHL (16-fold; p<0.0001) suggesting that this Aiolos transcript is highly expressed specifically in B-CLL cells Patients with high Aiolos expression (according to ROC-analysis) had a significantly longer treatment-free survival (TFS) and overall survival (OS) than patients with low Aiolos expression (median TFS: 119 versus 45 months, p=0.005; median OS: 321 versus 244 months, p=0.0065). Evaluation of several disease characteristics in association with the Aiolos expression status of the patients’ B-CLL cells showed no significant differences for ZAP-70 expression (p=0.28), CD38 expression (p=0.067), IgVH status (p=0.49) and Binet stage (p=0.13) suggesting no correlation of Aiolos expression with these already established adverse prognostic factors. In multivariate analysis low Aiolos expression was an independent prognostic factor with significance for trend (hazard ratio 1.413; p=0.069). Sequential analyses in a subset of 10 CLL patients revealed that Aiolos expression was relatively stable over time in the majority of patients. Conclusions: Here we demonstrate for the first time that the level of Aiolos expression is correlated with prognosis in B-CLL. The exact causes and consequences of this upregulation on the survival of CLL B-cells and the demonstrated better prognosis have yet to be determined. However, Aiolos may function as a tumor suppressor by controlling the cell cycle and DNA replication.

scholarly journals Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2124 ◽  
Author(s):  
Brigitte Bauvois ◽  
Elodie Pramil ◽  
Ludovic Jondreville ◽  
Elise Chapiro ◽  
Claire Quiney ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Normal Peripheral Blood ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Neutrophil Gelatinase

The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment.

An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis

2011 ◽  
Vol 70 (6) ◽  
pp. 1115-1121 ◽  
Author(s):  
Veronica Codullo ◽  
Helen M Baldwin ◽  
Mark D Singh ◽  
Alasdair R Fraser ◽  
Catherine Wilson ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Mononuclear Cells ◽  
Platelet Rich Plasma ◽  
Critical Role ◽  
Serum Levels ◽  
Pcr Analysis ◽  
Peripheral Blood Mononuclear ◽  
Matrix Deposition ◽  
Disease Subtype ◽  
Inflammatory Chemokines

ObjectivesSystemic sclerosis (SSc) is characterised by vasculopathy, an aberrantly activated immune system and excessive extracellular matrix deposition. Inflammatory chemokines control migration of cells to sites of tissue damage; their removal from inflamed sites is essential for resolution of the inflammatory response. The atypical chemokine receptor D6 has a critical role in this physiological balance. To explore potential deregulation of this system in SSc, inflammatory chemokine and D6 expression were compared with that in healthy controls (HC).MethodsSerum levels of inflammatory mediators were assessed by luminex analysis. Peripheral blood mononuclear cells (PBMCs) were used in molecular and immunocytochemical analysis. Platelet-rich plasma was collected and assessed by western blotting for D6 expression levels. Sex-matched HC were used for comparison.Results72 patients with SSc and 30 HC were enrolled in the study. The chemokines MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4 and IL-8/CXCL8 were significantly increased in patients with SSc, regardless of disease subtype and phase. Quantitative PCR analysis revealed a significant 10-fold upregulation of D6 transcripts in patients with SSc compared with controls, and this was paralleled by increased D6 protein expression in the PBMCs of patients with SSc. Platelet lysates also showed strong D6 expression in patients with SSc but not in controls. Importantly, high levels of D6 expression correlated with reduced levels of its ligands in serum.ConclusionsInflammatory chemokines and the regulatory receptor D6 are significantly upregulated in SSc and high D6 levels are associated with lower systemic chemokine levels, indicating that some patients control systemic chemokine levels using D6. These results suggest that chemokines may represent a therapeutic target in SSc.

Monoglycerides induce apoptosis in human leukemic cells while sparing normal peripheral blood mononuclear cells

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 292-294 ◽  
Author(s):  
Fabianne Philippoussis ◽  
Chantal Arguin ◽  
Véronique Mateo ◽  
Ann-Muriel Steff ◽  
Patrice Hugo
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Major Drawback ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Blood Mononuclear Cells

Abstract A major drawback of the current antineoplastic treatments is their lack of specificity toward cancer cells, because they are most often cytotoxic to normal cells, thus creating related side effects. Hence, the identification of new apoptosis-inducing agents, specifically targeting malignant cells while sparing their normal counterparts, is of crucial interest. We show here that monoglycerides, a family of lipids consisting of a single fatty acid attached to a glycerol backbone, induce cell death in several human leukemic cell lines. Importantly, treatment of primary leukemic cells, obtained from B-cell chronic lymphocytic leukemia patients, resulted in rapid apoptosis. In striking contrast, resting or activated human peripheral blood mononuclear cells from healthy individuals were resistant to the same treatment. Therefore, these compounds could represent potential antileukemic drugs or could allow for the design of novel therapeutic agents applied to leukemia.

scholarly journals Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1586-1594 ◽  
Author(s):  
M Dono ◽  
S Hashimoto ◽  
F Fais ◽  
V Trejo ◽  
SL Allen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Dna Sequences ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Specific Primers ◽  
Region Gene ◽  
Peripheral Blood Mononuclear ◽  
Ancestral Gene

Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha- expressing cDNA were present in greater amounts that unrelated (non- CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.

Novel Role of the TAL1/SCL Transcription Factor in Murine Monocytopoiesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1376-1376
Author(s):  
Soumyadeep Dey ◽  
David J. Curtis ◽  
Stephen Jane ◽  
Stephen J. Brandt
Keyword(s):  
Transcription Factor ◽  
Real Time ◽  
Real Time Pcr ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Pcr Analysis ◽  
Bhlh Transcription Factor ◽  
Lacz Gene ◽  
Macrophage Differentiation ◽  
In Cells

Abstract The basic helix-loop-helix (bHLH) transcription factor TAL1/SCL plays a critical role in hematopoiesis and vascular remodeling. A mouse Tal1 cDNA was first cloned from a bone marrow (BM) macrophage cDNA library, and we and others observed expression ofTal1 protein by BM mononuclear cells. To characterize Tal1 expression during monocyte/macrophage differentiation, we isolated common myeloid precursors (CMPs) from BM of 3-5 week old C57BL/6J mice and induced them to terminally differentiate according to a published method (Genes & Dev., 16:1721, 2002). Using real-time PCR analysis,Tal1 mRNA was expressed in a biphasic pattern from CMP to post-mitotic macrophage, including lipopolysaccharide- and interferon-ã-activated macrophages. To elucidate Tal1’sfunctions in murine monocytopoiesis we deleted the Tal1 gene in murine BM monocytes and monocytic precursors in culture. To that end, C57BL/6 mice with loxP sequences flanking the third coding exon of Tal1 were bred with C57BL/6 mice with a lacZ gene replacing Tal1 coding exons 1, 2, and 3. Tal1fl/fl/lacZ progeny were identified by PCR genotyping, and BM mononuclear cells were cultured with mouse interleukin-3 and macrophage colony-stimulating factor (M-CSF). To render the cells Tal1-null, Cre coding sequences were introduced with the MSCV-GFP retroviral vector and GFP-positive cells were then sorted and cultured with M-CSF alone. Real-time PCR analysis showed near-total abolition of Tal1 mRNA expression in Cre-transduced relative to vector-transduced cells. Gene expression analysis for other transcripts showed an approximately 4-foldreduction in Gata2 expression over the same culture period but no difference in Aml1,PU.1, Csfr1, Msr1 (mouse scavenger receptor), Cd68, or Il6ra. Biologically, the most significant effect of Tal1 knockout was on cell number, which increased by 80% in control cells but not at all in Tal1-null cells. Transduction of wild-type BM monocytes with MSCV-GFP-Cre (or the parental MSCV-GFP) vector had no effect on cell proliferation, precluding any nonspecific or toxic effect of Cre (or retroviral infection) in this cell type. Dye dilution analysis of virus-transduced cells with the fluorescent membrane-intercalating dye PKH26 revealed a delay and absolute reduction in proliferation of Tal1-null compared to control cells. In contrast, little or no difference was noted in annexin V staining ofTal1-null compared to heterozygous knockout (knock-in) cells, indicating a lack of effect on apoptosis. Finally, serial analysis of CD31 and Ly6c expression in differentiating Tal1hemizygous and nullizygous BM monocytes showed that loss of Tal1 caused a slight acceleration in terminal monocyte-macrophage differentiation. In summary, these studies confirm our earlier finding that the Tal1 gene is expressed in differentiating mouse BMmonocytes. In addition, they reveal a novel function of this bHLH transcription factor in proliferation of murine monocyte/macrophage precursors. Finally, they place Tal1upstream of Gata2 in cells of this lineage.

Increased Expression of PD-1 on CD4+ T Cells from Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4154-4154
Author(s):  
Mary M Sartor ◽  
David J Gottlieb
Keyword(s):  
T Cells ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Effector Memory ◽  
Cd4 Cells ◽  
Normal Peripheral Blood

Abstract Although the predominant finding in patients with chronic lymphocytic leukemia (CLL) is an expansion of monoclonal B lymphocytes, a polyclonal expansion of T cells co-exists in CLL patients. Allogenic stem cell transplants for CLL suggest that a significant graft versus leukaemia effect mediated through recognition of minor MHC or leukaemia specific antigens can be achieved. Since it appears that the immune system and probably T cells recognise CLL cells, it is possible that one or more T cell defects might contribute to the initiation or maintenance of a clone of CLL lymphocytes. PD-1 is a coinhibitory molecule that is expressed on T cells in patients with chronic viral infections. It has been suggested that PD-1 expression might be a marker of cell exhaustion due to antigenic overstimulation. We examined the expression of PD-1 and its naturally occurring ligands PD-L1 and PD-L2 on both B and T cells in patients with CLL and compared this with expression on normal peripheral blood mononuclear cells. We found that PD-1 was expressed on over 10% of CD4+ T cells in 7 of 9 cases of CLL (mean 22±16%) but not on CD4+ T cells in any of 9 normal donors (mean 0±0%), p=0.0009. There was no difference in PD-1 expression on CD8+ or CD14+ PBMCs from CLL patients and normal donors (for CD8+ 24±21% and 19±16% for CLL and normals; for CD14+ 58±16% and 71±31% for CLL and normals). More than 10% of CD5+/19+ CLL cells expressed PD-1 in 7 of 10 cases (mean 18±18%) while more than 10% of normal B cells from 6 of 7 donors also expressed PD-1 (mean 49±30%). We examined the expression of PD-1 on naïve, central memory, effector memory and terminally differentiated subsets of CD4+ cells (CD62L+CD45RA+, CD62L+CD45RA−, CD62L−CD45RA− and CD62L−CD45RA+ respectively) from CLL patients and normal donors. The expression of PD-1 was higher on CD4+ cells from CLL patients in all subsets. The effect was most prominent in the effector memory subset (mean 54±4% for CLL patients versus 26±17% for normal donors, p=0.02). We looked for expression of PD-L1 and PD-L2 on T cells, B cells, monocytes and NK cells from CLL patients and normal donors. PD-L1 was only expressed on monocytes (mean 30±23%) and NK cells (mean 14±19%) from CLL patients and on monocytes from normal donors (mean 35±26%). There was no expression of PD-L2 on any cell type in either CLL patients or normal donors. We conclude that there is increased expression of the co-inhibitory molecule PD-1 on CD4+ T cells in patients with CLL. Ligation of PD-1 by PD-L1 expressed on monocytes or NK cells could inhibit immune responses to tumor and infectious antigens leading to persistence of clonally expanded cells and predisposition to opportunistic pathogens.

scholarly journals Oncogene expression in autoimmune and normal peripheral blood mononuclear cells.

1986 ◽  
Vol 163 (5) ◽  
pp. 1292-1307 ◽  
Author(s):  
D M Klinman ◽  
J F Mushinski ◽  
M Honda ◽  
Y Ishigatsubo ◽  
J D Mountz ◽  
...  
Keyword(s):  
B Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Isolated Cells ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Additional Cell ◽  
Normal Controls

PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases.

Differential Expression of Adhesion Molecules and Chemokine Receptors Confers Increased Migrative Capacity to ZAP-70-Positive Subclones in CLL Primary Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3889-3889
Author(s):  
Marta Crespo ◽  
Cecilia del Carmen Carpio ◽  
Eva Calpe ◽  
Pau Abrisqueta ◽  
Carlos Palacio ◽  
...  
Keyword(s):  
Differential Expression ◽  
Adhesion Molecules ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Mononuclear ◽  
Expression Levels

Abstract Abstract 3889 Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by the accumulation and proliferation of mature B-lymphocytes. CLL clinical course is extremely heterogeneous; patients with worse prognosis can be identified by the presence of high ZAP-70 expression. Increasing evidence indicates that the microenvironment plays a critical role providing survival and proliferative signals to CLL cells. In this sense, ZAP-70 protein expression has been related to increased capability of the cells to respond to several survival and migration signals provided by the cellular microenvironment through chemokines and cell-to-cell direct contact. We aimed to analyze the expression levels of several adhesion molecules and chemokine receptors potentially involved in CLL pathogenesis and progression in subclones of CLL cells with high or low ZAP-70 expression within the same patient. For this we obtained peripheral blood mononuclear cells from 40 patients diagnosed with CLL at our institution after informed consent. We then performed a flow cytometry analysis with 7 parameters that allowed for the measurement of the expression of different molecules in CD19+/CD5+ CLL cells with high or low ZAP-70 expression. The expression level of ZAP-70 protein in CD3+ T lymphocytes was used to set the threshold between CLL cells with low or high ZAP-70 expression (Figure 1). Using this approach we analyzed the differential expression of CCR7, CXCR4, CXCR5, CD44, CD49d and CD62L. Interestingly, we found that the expression levels of all the adhesion molecules and cytokine receptors analyzed were significantly higher in those CLL subclones with high ZAP-70 expression compared to CLL cells with low ZAP-70 expression within the same patient (Table 1), suggesting that the relationship with the microenvironment is not uniform across the CLL clone, but those CLL cells with higher expression of ZAP-70 have increased potential to receive signals from other cells. In order to analyze if this could translate into an increased capacity of the CLL cells with high ZAP-70 expression to migrate towards chemokines, we performed an in vitro transmigration assay across bare polycarbonate filters using primary CLL cells from 7 of the patients. We allowed the cells to migrate for 6 hours towards a media containing 1 μg/ml of CCL21 (the ligand of CCR7) and proceed to measure the percentage of CD19+/CD5+ CLL cells with ZAP-70 expression among those cells that had transmigrated and to compare it with the percentage of ZAP-70-positive cells within the ones that did not migrate. Of note, for all the cases analyzed, we observed that the percentage of ZAP-70-positive cells was significantly higher in the cells that had migrated compared to the cells present in the upper chamber (p=0.018) indicating that ZAP-70-positive CLL cells have an enhanced ability to respond to and to migrate towards CCL21. In conclusion, the differential expression of adhesion molecules and chemokine receptors in primary CLL cells with higher expression of ZAP-70 can influence their relationship with the microenvironment and confers them a higher migratory potential towards CCL21.Figure 1:Figure 1:. Table 1:MFI: mean fluorescence intensity SEM: standard error of the meanMean MFI ± SEM Low ZAP-70 CLL cellsMean MFI ± SEM High ZAP-70 CLL cellsPaired samples t-test p valueCCR7163.56 ± 11.3178.20 ± 13.40.007CXCR4263.01 ± 36308.95 ± 45.30.004CXCR5604.02 ± 62.6652.89 ± 67.50.001CD441081.11 ± 76.91210.8 ± 82.5>0.001CD49d58.43 ± 16.169.6 ± 17.6>0.001CD62L33.81 ± 8.947.63 ± 12.1>0.001 Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1365-1374 ◽  
Author(s):  
S Zupo ◽  
L Isnardi ◽  
M Megna ◽  
R Massara ◽  
F Malavasi ◽  
...  
Keyword(s):  
B Cells ◽  
Fluorescence Intensity ◽  
Lymphocytic Leukemia ◽  
Relative Fluorescence Intensity ◽  
Normal Peripheral Blood ◽  
Cd38 Expression ◽  
Intensity Range ◽  
Group I ◽  
Contrast Exposure ◽  
Group Ii

The expression of CD38 by B cells chronic lymphocytic leukemia (B-CLL) was studied in 20 untreated patients. The cells expressed abundant CD38 (relative fluorescence intensity range, 6 to 15) in 6 cases (group I patients), whereas CD38 expression was low to absent (relative fluorescence intensity range, 0 to 3) in the remaining cases (group II patients). Exposure of the cells from group I patients to goat antihuman mu chain antibodies (Ga mu-ab) resulted in the elevation of intracellular free Ca2+ concentration([Ca2+]i) followed by apoptosis. In contrast, exposure of group II cells to Ga mu-ab was not followed by increased levels of [Ca2+]i, programmed cell death or cell proliferation. No differences in the expression of surface IgM were noted in the two groups of B-CLL cells. Normal peripheral blood B cells, which expressed low to absent CD38, were capable of mobilizing [Ca2+]i and of proliferating after exposure to Ga mu-ab. The collected data suggest that, although group I B-CLL cells were able to transduce the signals delivered by IgM crosslinking, this pathway was severely impaired in group II B-CLL cells. However, unlike that observed in normal circulating B cells, stimulation of group I cells with Ga mu-ab resulted in apoptosis rather than proliferation. CD38 did not appear to be directly involved in [Ca2+]i mobilization induced by Ga mu-ab in group I B-CLL cells because their exposure to anti-CD38 monoclonal antibodies failed to cause [Ca2+]i mobilization or to block the [Ca2+]i response induced by Ga mu-ab. These data indicate that CD38 expression identified a particular subset of B-CLL cells with defined functional properties, including the propensity to undergo apoptosis.

BAFF Support Survival of Chronic Lymphocytic Leukemia B Cells by a Pathway Independent of Stromal Derived Factor-1α.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1908-1908
Author(s):  
Mitsufumi Nishio ◽  
Nobuhiro Tsukada ◽  
Shinichi Kitada ◽  
Junko Ohata ◽  
Nathan J. Zvaifler ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
Mononuclear Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Peripheral Blood Mononuclear ◽  
Cells Cultured

Abstract We examined the peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL) for expression of B cell-activating factor of the TNF family (BAFF). Isolated CLL B cells had significantly lower levels of BAFF mRNA than did non-separated PBMC. Most of the BAFF mRNA in PBMC was due to contaminating CD14+ cells that previous studies found could differentiate into “nurselike” cells (NLC) when cultured with CLL B cells in vitro. We found NLC expressed high-levels of BAFF and stromal cell-derived factor-1 alpha (SDF-1α), in contrast to CLL B cells. CLL B cells cultured with exogenous recombinant human BAFF (rhBAFF), SDF-1α, or NLC sustained significantly greater viability than isolated CLL B cells cultured alone. The effect(s) of rhBAFF on leukemia cell survival appeared additive and distinct from that of SDF-1α, which in contrast to rhBAFF induced leukemia-cell phosphorylation of p44/42 mitogen-activated protein-kinase (ERK 1/2) and phosphorylation and activation of AKT at Ser473. However, rhBAFF, but not SDF-1α, could induce processing of p100 NF-κB2 to p52 and, like NLC, enhance and/or maintain CLL-cell expression of the anti-apoptotic protein Mcl-1. We conclude that BAFF can function in a paracrine manner to support leukemia cell survival via mechanisms that are distinct from those of SDF-1α and that NLC use multiple distinct pathways to support CLL-cell survival.

Sign in / Sign up

Export Citation Format

Share Document