[Assessment of selected markers of apoptosis and angiogenesis in chronic lymphocytic leukemia].
BACKGROUND
Search for new prognostic markers in order to improve prognostic accuracy and predict clinical outcome at the time of dia-gnosis 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 (TNFα) and transforming growth factor β 1 (TGFβ1) using commercially available enzyme linked immunosorbent assay; furthermore, 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 TNFα in patients with CLL compared to the control group (p < 0.0001); high expression of TNFα was associated with unfavourable prognosis: significantly higher concentrations were found in patients with Rai highrisk 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 TNFα than those with stable clinical course (p = 0.0009); time to treatment was significantly shorter in patients with higher TNFα (p = 0.0049). Higher TGFβ1 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 TGFβ1 levels than those with stable course (p = 0.0014) and time to treatment was significantly longer in patients with higher TGFβ1 (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 TNFα and massive lymphadenopathy (p = 0.036, resp. p = 0.047).


CONCLUSIONS
Based on our results, TNFα and TGFβ1 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.
M
M
Motyčková
L
L
Smolej
C
C
Andrýs
V
V
Rezáčová
V
V
Reháček
M
M
Simkovič
D
D
Belada
P
P
Zák
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000097:blood*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000097:blood; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000097:blood; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000097:blood; D012016:Reference Values; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D051746:ZAP-70 Protein-Tyrosine Kinase
D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II