Spontaneous apoptosis and proliferation detected by BCL-2 and CD71 proteins are important progression indicators within ZAP-70 negative chronic lymphocytic leukemia

Poeta, Giovanni Del; Principe, Maria Ilaria Del; Maurillo, Luca; Rossi, Francesca Maria; Buccisano, Francesco; Ammatuna, Emanuele; Simotti, Cristina; Zucchetto, Antonella; Catalano, Gianfranco; Bulian, Pietro; Bruno, Antonio; Venditti, Adriano; Fabritiis, Paolo de; Gattei, Valter; Amadori, Sergio

doi:10.3109/10428190903350421

Cited by 17 publications

(9 citation statements)

References 49 publications

(57 reference statements)

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“…First, we observed a significant lower bax/bcl-2 ratio in CD38 and CD49d positive patients. It is well known that CD38 and CD49d overexpression are adverse prognostic markers in CLL 19,34,35 and it has been reported that interactions involving CD38 and CD49d prevent spontaneous and drug-induced apoptosis of normal and neoplastic B cells. 36 Interestingly, co-culture of CLL cells with human vascular endothelial cells determined a simultaneous overexpression of CD38, CD49d bax/bcl-2 ratio in CLL haematologica | 2016; 101(1) Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…We had previously demonstrated that the quantification of bcl-2 and bax, measuring fluorescence intensity by flow cytometry, is technically adequate and useful for a correct evaluation of clinical and prognostic correlations both in acute myeloid leukemia 17 and in CLL. 19 In the present study, we used a well-standardized and simple flow cytometric method for bcl-2 and bax determinations. In particular the methodological feasibility and reproducibility of this flow cytometric approach was confirmed by the finding that superimposable results of bax/bcl-2 ratios were obtained in a series of CLL cases for which bax/bcl-2 measures from fresh PB samples were repeated in two different laboratories (Online Supplementary Table S1), or when two directly conjugated anti-bax MoAbs were employed (Online Supplementary Tables S2 and S3).…”

Section: Discussionmentioning

confidence: 99%

“…The results were performed by gating lymphoid cells on a SSC versus FSC plot ( Figure 1A and E) and examining bcl-2 and bax as mean fluorescence intensity (MFI) on CD19 positive/CD5 positive cells ( Figure 1C, D, G and H). 19 Bcl-2 and bax were then evaluated as relative mean fluorescence intensities (rMFIs), calculated as the ratio between bcl-2 or bax MoAbs MFI and non-specific MoAb MFI on B cells. Finally, the results were expressed as an index (bax/bcl-2) obtained by dividing rMFI bax and rMFI bcl-2.…”

Section: Bcl-2 and Bax Expressionmentioning

confidence: 99%

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Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Principe

Bittolo

et al. 2015

Haematologica

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In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. ABSTRACT

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Bcl-2 and Bax Expressionmentioning

confidence: 99%

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Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Principe

Bittolo

et al. 2015

Haematologica

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“…The pathological therapy response in breast cancer patients is reflected by the presence of apoptotic disseminated tumor cells (26). In chronic lymphocytic leukemia, inhibition of spontaneous apoptosis determines a worse prognosis (27). Therefore, investigating the mechanism of spontaneous apoptosis occurring in the gastric carcinoma cells in ascites will help to improve the prognosis of patients with gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Immune clearance gastric carcinoma cells in ascites by activating caspase-9-induced apoptosis

Fang¹,

Lou

Wang³

et al. 2011

Apmis

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Floating gastric adenocarcinoma cells in ascitic fluid are the main cause of peritoneal dissemination. Activation of apoptosis is an important mechanism by which tumor cells are eliminated by the immune surveillance system. Hence, we examined caspase-9 expression and the apoptosis in gastric adenocarcinoma cells in ascitic fluid using immunohistochemistry, real-time polymerase chain reaction and in situ cell death detection kits, flow cytometry. The results revealed strong expression of caspase-9 in 58.49% (31/53) malignant cells and a relatively weak expression of caspase-9 in 41.51% (22/53) malignant cells. The proportion of apoptotic cells in 31 malignant cases with strong caspase-9 expression (35.14 ± 3.42)% was significantly higher than that in 22 malignant cases with relatively weak caspase-9 expression (17.29 ± 7.62)% or in mesothelial cells (10.76 ± 4.21%; p < 0.05). Kaplan-Meier survival curves demonstrated that the patients with low caspase-9 expression showed significantly shorter survival (p < 0.05) than those with high caspase-9 expression. These findings suggest that immune clearance gastric carcinoma cells in ascites activated by caspase-9 helped to improve the prognosis of patients with gastric cancer.

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“…In this issue, Del Poeta [7] attempt to extend the prognostic factor armentarium that has been established for CLL by studying the expression of CD71 (the transferring receptor which has been correlated with proliferative activity) and BCL-2 by FACS in a relatively large cohort of patients with CLL. The group shows an association of high BCL-2 and CD71 expression with short lymphocyte doubling time, prior treatment and poor outcome with respect to progression free survival (PFS) and overall survival (OS) (borderline) in univariate analysis.…”

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confidence: 99%