Vnitr Lek 2013, 59(9):782-793

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

M. Motyčková^1,*, L. Smolej¹, C. Andrýs², V. Řezáčová², V. Řeháček³, M. Šimkovič¹, D. Belada¹, P. Žák¹

¹ IV. interní hematologická klinika Lékařské fakulty a FN Hradec Králové, přednosta doc. MUDr. Pavel Žák, Ph.D.

² Ústav klinické imunologie a alergologie Lékařské fakulty UK a FN Hradec Králové, přednosta prof. RNDr. Jan Krejsek, CSc.

³ Transfuzní oddělení Lékařské fakulty UK a FN Hradec Králové, přednosta prim. MUDr. Vít Řeháček

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.

Keywords: chronic lymphocytic leukemia; prognosis; TNF-α; TGF-β1; TGFβRII; FGFR2; apoptosis; angiogenesis

Received: February 18, 2013; Accepted: April 21, 2013; Published: September 1, 2013  Show citation