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Assessment of selected markers of apoptosis and angiogenesis in chronic lymphocytic leukemia


Authors: M. Motyčková 1;  L. Smolej 1;  C. Andrýs 2;  V. Řezáčová 2;  V. Řeháček 3;  M. Šimkovič 1;  D. Belada 1;  P. Žák 1
Authors‘ workplace: IV. interní hematologická klinika Lékařské fakulty a FN Hradec Králové, přednosta doc. MU Dr. Pavel Žák, Ph. D. 1;  Ústav klinické imunologie a alergologie Lékařské fakulty UK a FN Hradec Králové, přednosta prof. RNDr. Jan Krejsek, CSc. 2;  Transfuzní oddělení Lékařské fakulty UK a FN Hradec Králové, přednosta prim. MU Dr. Vít Řeháček 3
Published in: Vnitř Lék 2013; 59(9): 782-793
Category: Original Contributions

Overview

Introduction:
Search for new prognostic markers in order to improve prognostic accuracy and predict clinical outcome at the time of dia­gnosis has recently become one of the major trends in chronic lymphocytic leukemia (CLL).

Patients and methods, aim of study:
The aim of our study was assessment of selected markers of apoptosis and angiogenesis and their potential as new prognostic factors. We evaluated serum levels of tumor necrosis factor α (TNF‑α) and transforming growth factor β‑ 1 (TGF‑β1) using comercially available enzyme‑linked immunosorbent assay; furthemore, we quantified expression of type II receptor for transforming growth factor beta (TGFβRII) and type 2 receptor for fibroblast growth factor‑ 2 (FGFR2) on CLL cells using flow cytometry analysis in 75 previously untreated patients with CLL (47 males and 28 females, median age, 65 years, range 38– 82) and healthy donors.

Results:
We found significantly elevated TNF‑α in patients with CLL compared to the control group (p < 0.0001); high expression of TNF‑α was associated with unfavourable prognosis: significantly higher concentrations were found in patients with Rai high‑risk group compared to low and intermediate-risk group (p = 0.0008 and p = 0.0097), with high serum β2- microglobulin (p = 0.045), massive lymphadenopathy (p = 0.0083), unmutated genes for variable region of immunoglobulin heavy chain (IgVH) (p = 0.041) and unfavourable cytogenetic aberrations (p = 0.0014). In addition, patients with progressive CLL had significantly higher TNF‑α than those with stable clinical course (p = 0.0009); time to treatment was significantly shorter in patients with higher TNF‑α (p = 0.0049). Higher TGF‑β1 concentrations were associated with favourable subgroups: with Rai low‑ risk group compared to high‑risk group (p = 0.011), patients without massive lymphadenopathy (p = 0.041), patients with mutated IgVH (p = 0.012) and ZAP‑ 70 negativity (zeta‑associated protein of 70 kilodaltons) (p = 0.044). Patients with progressive CLL had significantly lower TGF‑β1 levels than those with stable course (p = 0.0014) and time to treatment was significantly longer in patients with higher TGF‑β1 (p = 0.016). Patients with Rai high‑risk group had significantly lower TGFβRII expression than those with low‑ risk group (p = 0.022). The prognostic significance of FGFR2 was not found. Significant and independent prognostic factors for overall survival were high serum concentrations of TNF‑α and massive lymphadenopathy (p = 0.036, resp. p = 0.047).

Conclusion:
Based on our results, TNF‑α and TGF‑β1 possess prognostic significance in CLL; further research in this direction may also be important therapeutically, because these signal pathways could serve as possible treatment targets.

Key words:
chronic lymphocytic leukemia –  prognosis –  TNF‑α –  TGF‑β1 –  TGFβRII –  FGFR2 –  apoptosis –  angiogenesis


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