Angiopoietin-2 mRNA Expression Is Elevated in Chronic Lymphocytic Leukemia Patients with Poor Prognostic Features

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4182-4182
Author(s):  
Filip Vrbacky ◽  
Lukas Smolej ◽  
Vladimira Vroblova ◽  
Sona Pekova ◽  
Monika Hrudkova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Statistical Significance ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Prognostic Features ◽  
Angiopoietin 2

Abstract Several studies have demonstrated potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiogenic activator angiopoietin-2 (Ang-2) was recently reported in CLL but data regarding prognostic significance of Ang-2 in CLL is limited. Therefore, we evaluated potential relationship between Ang-2 expression and other prognostic factors in patients with CLL. Ang-2 mRNA was quantified by real-time quantitative PCR in purified mononuclear cells of 33 untreated CLL patients. Ang-2 transcript levels were further analyzed with regard to clinical stage, disease course, IgVH mutation status, CD38 and ZAP-70 expression. Elevated Ang-2 mRNA was detected in 12 cases; twenty-one patients had very low or undetectable levels of Ang-2 transcript. High Ang-2 mRNA levels were significantly associated with unmutated IgVH genes (p=0.010) and high CD38 expression (p=0.011) but not with ZAP-70 expression (p=0.784), Rai stage (p=0.305) or stable vs. progressive clinical course (p=0.443). Interestingly, there was a trend towards shorter progression-free survival in patients with high Ang-2 expression, but it did not reach statistical significance (median 15 months vs. not reached; p=0.090). In conclusion, our data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features.

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.

Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 Chronic Lymphocytic Leukemia

2007 ◽  
Vol 25 (12) ◽  
pp. 1576-1580 ◽  
Author(s):  
Ana Muntañola ◽  
Francesc Bosch ◽  
Pedro Arguis ◽  
Eduardo Arellano-Rodrigo ◽  
Carmen Ayuso ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Chronic Lymphocytic Leukemia ◽  
Early Stage ◽  
Strong Predictor ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Clinical Information ◽  
Lymphocytic Leukemia ◽  
Abdominal Ct ◽  
Work Up

Purpose Whether computed tomography (CT) should be routinely included in the diagnostic work-up in patients with chronic lymphocytic leukemia (CLL) has not yet been determined. The aim of this study was to analyze the prognostic significance of abdominal CT in patients with CLL in Rai clinical stage 0. Patients and Methods Abdominal CT was performed at diagnosis in 140 patients consecutively diagnosed with CLL in Rai stage 0 disease. Results An abnormal abdominal CT was found in 38 patients (27%). Abnormal CT correlated with increased bone marrow infiltration (P = .024), high lymphocyte count (P = .001), increased ZAP-70 expression (P = .003), and short lymphocyte doubling time (LDT; P = .007). Patients with abnormal CT progressed more frequently and had a shorter time to progression than those with normal CT (median, 3.5 years v not reached, respectively; P < .001) and required earlier treatment intervention. In a multivariate analysis, only high ZAP-70 expression (relative risk = 3.60) and an abnormal abdominal CT (RR = 2.71) correlated with disease progression. Conclusion In this series, an abnormal abdominal CT was a strong predictor of progression in patients with early-stage CLL. The inclusion of CT scans in the initial work-up of patients with early clinical stage on clinical grounds can, therefore, provide relevant clinical information.

Global Methylation Provides Independent Prognostic Information in Chronic Lymphocytic Leukemia and Is Associated with a Microrna Signature

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3873-3873
Author(s):  
Alfons Navarro ◽  
Gerardo Ferrer ◽  
Marina Díaz-Beyá ◽  
Carmen Muñoz ◽  
Rut Tejero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Mirna Expression ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Surrogate Marker ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Global Methylation

Abstract Abstract 3873 Introduction: Disruption of normal DNA methylation, including both gene specific hypermethylation and genome-wide hypomethylation, is found in most malignant tumors. Most epigenetic studies in chronic lymphocytic leukemia (CLL) have been focused in CpG islands and gene promoter regions, and have identified hypomethylated genes, such as BCL2 or TCL1, and hypermethylated genes, such as GRM7. However, the quantification of overall methylation measured as levels of 5-methylCytosine (5mC) has been poorly explored. As compared to their normal counterparts (CD19+ B cells), overall hypomethylation has been observed in CLL neoplastic cells. Importantly, the overall methylation varies among patients but its clinical significance has not been widely investigated. In addition, it is known that microRNA (miRNA) expression is altered in CLL, and that and epigenetic mechanisms, such as methylation, can affect miRNA expression. Aim: To investigate the prognostic impact of overall methylation in patients with CLL and to analyze the correlation of 5mC levels with miRNAs expression. Methods: We analyzed 73 CLL patients (median age, 69 [range, 34–86]; 43% males) diagnosed in our institution between 1992 and 2007. The median follow up was 10.5 years. The level of global methylation in total DNA was estimated after determination of percentage of 5mC using anti-5mC monoclonal antibodies (MethylFlash Methylated DNA Quantification Kit, Epigentek). The expression of 377 mature miRNAs was analyzed using TaqMan Array Human MicroRNA A Card v2.0 (Applied Biosystems). Statistical analysis was performed with SPSS version 15.0.1 and R software version 2.9.0. MaxStat package of R were used to determine the optimal cutoffs and Quantitative trail function in BRB array tools to correlate miRNA expression and methylation levels. Results: The analysis of methylation levels showed a wide distribution of methylation degree among patients (median: 3.02%, range: 0.58–6.14%). From the clinical standpoint, methylation levels were only correlated with Binet clinical stage, patients with C stage showing a higher degree of methylation (p=0.015). Using MaxStat, we identified two cutoffs which classified patients as having low, medium or high degree of methylation. Mean progression-free survival (PFS) was 8.4 years (95% CI: 6.4–10.4), 6.2 years (95% CI: 4.7–7.7) and 3.2 years (95% CI: 2.4–4.8) for patients with low, medium, and high methylation levels, respectively (p=0.013). In the multivariate analysis for PFS (including ZAP70, IGHV, Age≤65, cytogenetics and global methylation), high ZAP70 expression (HR: 3; 95%CI: 1.1–7.9; p=0.026) and high global methylation (HR: 5.4 95%CI: 1.7–17.1; p=0.004) were independent unfavorable prognostic factors, while a significant trend was observed for high-risk cytogenetics (17p-, 11q-, +12) (p=0.054). Interestingly, methylation levels retained its prognostic significance in subgroup analysis: clinical stage A (p=0.06) and B/C (p=0.009); mutated (p=0.008) and unmutated IGHV (p=0.028); low (p=0.028) and high ZAP70 (p=0.001); and low-risk (normal karyotype, 13q-)(p=0.008) and high-risk (17p-, 11q-, +12) cytogenetics (p=0.001). Finally, we identified a 4-miRNA signature associated with global methylation levels: miR-103 (Spearman correlation [SC]: −0.821;p=0.03), miR-132 (SC: 0.786;p=0.05), miR-494 (SC: −0.786; p=0.02), and miR-193a-5p (SC: 0.786; p=0.05). Interestingly, miR-103, miR-132 and miR-494 are located in subtelomeric regions, which are known to be more susceptible to overall methylation changes. Conclusions: In this study, the degree of global DNA methylation was an independent prognostic factor for PFS in patients with CLL. The analysis of overall methylation could be useful not only for the prognosis of patients with CLL but also in the monitoring of clinical trials in which hypomethylating agents (e.g., decitabine) are being investigated as CLL therapy. The correlation between overall methylation levels and certain miRNAs may be a surrogate marker of epigenetic lesions and deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Association of Bax Expression and Bcl2/Bax Ratio with Clinical and Molecular Prognostic Markers in Chronic Lymphocytic Leukemia

2016 ◽  
Vol 35 (2) ◽  
pp. 150-157 ◽  
Author(s):  
Ksenija Vucicevic ◽  
Vladimir Jakovljevic ◽  
Natasa Colovic ◽  
Natasa Tosic ◽  
Tatjana Kostic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Prognostic Markers ◽  
Statistical Significance ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Mutational Status

Summary Background: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. Aim: The aim of this study was to investigate the association of pro-apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. Methods: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. Results: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=−0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. Conclusions: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

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.

Disruption of a Functional Relationship Between PU.1 and Mir-155 during the Pathogenesis of Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3148-3148
Author(s):  
Tomas Stopka ◽  
Karin Vargova ◽  
Adela Berkova ◽  
Juraj Kokavec ◽  
Marek Trneny ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Inverse Correlation ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Mononuclear ◽  
Prognostic Features ◽  
Ets Family ◽  
Atm Gene ◽  
Differentiation And Proliferation

Abstract Role of small non-coding microRNAs (miR) in hematopoiesis has been recently established by work demonstrating critical importance of miR-223 for granulocytic development (Johnnidis 2008) and miR-155 in lymphocytic differentiation (Thai 2007) in mice. The importance of miR-155 is further supported by several independent studies demonstrating its increased levels in human diffuse large B-cell lymphoma (Eis 2005, Kluvier 2005, Volinia 2006, Lawrie 2007, Rai 2008) and in chronic lymphocytic leukemia (CLL) (Fulci 2007, Marton 2008). PU.1 is ETS family transcription factor involved in myelo-lymphoid differentiation and is directly negatively regulated by miR-155 (Vigorito 2007). Studying primary CLL (N=27) and normal (N=13) peripheral blood mononuclear cells, we found significantly increased miR-155 levels and also demonstrate that PU.1 levels are significantly decreased. Next, we have tested genes that are targets of both miR-155 and PU.1 including CSF1R and FOS and again demonstrated their significantly decreased expression in CLL. Using gene expression profiling of CLL peripheral lymphocyte samples compared to normal controls, we have determined significant downregulation of the PU.1 mRNA and of numerous miR-155 targets previously reported to be required for myelo-lymphoid differentiation. These findings suggest that the relationship between PU.1 and miR-155 becomes disrupted in CLL. This in turn leads to overexpression of miR-155, reduced levels of PU.1 and of numerous miR-155 targets (N=2481 and N=400 respectively) and to inhibition of PU.1 regulated differentiation and proliferation programs. Next, we correlated negative cytogenetic prognostic features (p53 and ATM gene deletion detected by FISH) of the CLL patients with the miR-155 and PU.1 levels, In a relatively small-size patient cohort studied so far, the low ratios of PU.1/miR- 155 levels are similarly distributed among low, intermediate and high risk CLL patients, suggesting that inverse correlation of PU.1 and miR-155 represents a hallmark of CLL and likely represents a primary event during CLL pathogenesis.

Safety and Efficacy Of Abbreviated Induction With Only 4 Cycles Of Fludarabine (F), Cyclophosphamide (C) and Rituximab (R) In Physically Fit Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Early Complete Remission (CR) With Undetectable Minimal Residual Disease (MDR)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2886-2886
Author(s):  
Carolina Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Adriana Galeano ◽  
Francisco Lastiri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Clinical Stage ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Blue Laser ◽  
Minimal Residual

Abstract Background Chemoimmunotherapy with 6 cycles of FCR is considered standard therapy for physically fit patients (pts) with Chronic Lymphocytic Leukemia (CLL). Many pts are unable to complete planned treatment, due to treatment related complications. Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher S et al. Leukemia, 2009). Achieving a negative MRD is therefore a mayor endpoint in treatment. Patients and methods From 4/2003, 39 physically fit pts with CLL who had IWCLL-NCI criteria for initiating treatment started therapy with FCR in our institution. Eleven pts had previously received chlorambucil/prednisone and 28 were not previously treated. Median age at start of therapy was 63 years (34-80), Binet´s clinical stage were A/B: 22 pts (56%) and C: 17 (44%). The CD38 expression was positive (>7% of cells) in 23 (59%) and negative in16 (41%) of the pts. After 4 courses of FCR response was assessed in peripheral blood (PB) or bone marrow (BM) using three colour flow Cytometry. Negative MRD was defined as < 0,1% of light chain restricted CD5+CD19+ B cells in PB and BM as assesed collecting 100000 CD19 cells in a three colour cytometer (FacsScalibur- blue laser ). All these patients stopped therapy after evaluation due to early CR with eradication of MRD. Results All patients had negative MRD in peripheral blood, 35 were also evaluated in bone marrow, 29 showed CR and 6 nodular partial remission (NPR). Neutropenia and infectious events grade 3-4 were observed in 24% and 7% of all the courses respectively. No pts died of toxicity. After a median follow-up of 81 months (4.6-120), progression free survival (PFS) and overall survival (OS) at 72 months was 51% and 75% respectively. Five pts died of progressive disease and 3 of a secondary neoplasm. Conclusion Stopping therapy in patients who achieve negative MRD after 4 cycles of FCR is safe and induces durable remission with a PFS and OS of 51% and 75% at 72 months exposing them to less chemotherapy. Large randomized trials are necessary to confirm this data. Disclosures: Pavlovsky: Novartis: Speakers Bureau; BMS: Speakers Bureau.

Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Maria Ilaria Del Principe ◽  
Giovanni Del Poeta ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Adriano Venditti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Mutational Status ◽  
Staging Systems ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P < .001), in CD38+ (P < .001) and in sCD23+ patients (P < .001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70–/CD38– or ZAP-70– patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38– or mutated showed a shorter PFS, whereas ZAP-70– patients even if CD38+ or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgVH gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70+ patients.

scholarly journals Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia

Blood ◽  
1991 ◽  
Vol 78 (7) ◽  
pp. 1795-1802 ◽  
Author(s):  
CH Geisler ◽  
JK Larsen ◽  
NE Hansen ◽  
MM Hansen ◽  
BE Christensen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Fluorescence Intensity ◽  
Mononuclear Cells ◽  
Clinical Stage ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Significant Difference ◽  
Prognostic Importance ◽  
Cell Chronic Lymphocytic Leukemia

Blood mononuclear cells from 540 newly diagnosed, unselected patients with B-cell chronic lymphocytic leukemia (CLL) were examined by immunofluorescence flow cytometry for a panel of surface membrane markers, including IgM and IgD, the monoclonal antibodies anti-CD3, -5, -20, -21, -22, -FMC7, and, for the final 125 patients, anti-CD23. There were 503 CD5+ and 37 CD5- cases. In the CD5+ cases, the cells typically expressed IgM, IgD, CD20, CD21, CD22, and CD23. In univariate analysis, age, clinical stage, IgM-fluorescence intensity, CD23, and FMC7 had significant prognostic importance, with high IgM-fluorescence intensity, high FMC7, and low CD23 expression being associated with a short survival. There was no significant difference in survival between 351 cases expressing IgMD and 55 cases expressing IgM without IgD, or between kappa and lambda light chain monoclonal cases. CD20, CD21, and CD22 had no prognostic importance. In Cox multiple regression analyses, age, CD23, IgM-fluorescence intensity, and clinical stage (International Workshop System) had independent prognostic importance. Thus, besides clinical variables, CD23 and IgM intensity might be useful prognostic markers in the management of CD5+, B-cell CLL. The survival of CD5- patients was on the borderline of being significantly shorter than that of CD5+ patients. The majority of the CD5- cases were FMC7+, CD23-, had strong IgM fluorescence, and had splenomegaly.

Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4122-4129 ◽  
Author(s):  
Paola Secchiero ◽  
Elisa Barbarotto ◽  
Mario Tiribelli ◽  
Carlotta Zerbinati ◽  
Maria Grazia di Iasio ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Apoptotic Pathway ◽  
Mitochondrial Potential ◽  
Peripheral Blood Mononuclear ◽  
P53 Pathway ◽  
Cell Chronic Lymphocytic Leukemia

Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-cell chronic lymphocytic leukemia (B-CLL). However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells. In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19+ B-CLL cells, but not on normal CD19+ B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors. Among 29 B-CLL samples examined, only one was resistant to nutlin-3–mediated cytotoxicity. The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway. Among several genes related to the p53 pathway, nutlin-3 up-regulated the steady-state mRNA levels of PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP53I3/PIG3, and GADD45. This profile of gene activation showed a partial overlapping with that induced by the genotoxic drug fludarabine. Moreover, nutlin-3 synergized with both fludarabine and chlorambucil in inducing B-CLL apoptosis. Our data strongly suggest that nutlin-3 should be further investigated for clinical applications in the treatment of B-CLL.

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