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  • 1
    Abstract: BACKGROUND: Tumor necrosis factor (TNF) receptor family members play a key role in the regulation of biological functions such as differentiation, proliferation and apoptosis of various cell types. MATERIALS AND METHODS: We studied co-expression profiles of death receptors from the TNF family [TNF-related apoptosis-inducing ligand receptor (TRAILR) 1 to 3, TNF receptor 1 (TNFR1) and FAS receptor (FAS)] on peripheral blood blasts from 46 patients with acute myeloid leukemia (AML) at first diagnosis by flow cytometry and correlated the obtained specific fluorescence indices (SFI) with morphological, cytogenetic and clinical parameters. RESULTS: We found that the expression of TRAILR2 and R3 was significantly increased in unfavorable risk groups, according to the National Comprehensive Cancer Network. Additionally, cut-off analyses for TRAILR2 and TNFR1 showed significantly shorter overall survival, earlier disease onset, higher proportions of cases with unfavorable prognosis and higher probability of relapse when SFIs were above the established cut-off. CONCLUSION: We demonstrate that high co-expression of death receptors on blasts is an independent predictor of poor prognosis in AML.
    Type of Publication: Journal article published
    PubMed ID: 26124353
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  • 2
    Abstract: BACKGROUND: Co-stimulatory receptor (COR) and ligand (COL) expression on immune effectors are known to be relevant for immunological interactions and might be of prognostic relevance if expressed on acute myeloid leukemia (AML) blasts as reported for receptors of the tumor necrosis factor receptor family. AIM AND METHODS: Antigen expression profiling of COR (RANK, PD-1), COL (RANK-L, PD-1L), and HLA-ABC-antigens on blasts from 90 AML-patients at first diagnosis was performed by flow cytometry (SFI-Level characterization) and findings were correlated with clinical parameters. RESULTS: RANK expression was higher in immature compared to mature FAB groups (P = 0.08). As a monocytic marker, we identified HLA-ABC (P = 0.07). Prognostic analysis revealed a higher probability of overall survival in cases with lower RANK-L expression (〈1.6 and 〉/=1.6, 15.6 vs. 12.2 months, P = 0.008, hazard ratio 0.36, P = 0.008). No significant impact of PD-1/L expression for patients'(pts) survival was seen but a correlation of PD-1 with a secondary AML (P = 0.03). Prolonged disease-free survival however correlated with higher PD-1 expression (〉/=1.1 vs. 〈1.1, 31.4 vs. 12.7 months; P = 0.03). CONCLUSION: Our study revealed that RANK-L is a promising marker to forecast pts' prognosis in AML. Immune checkpoint receptor PD-1/L as well as RANK and HLA-ABC did not show an impact on pts' survival.
    Type of Publication: Journal article published
    PubMed ID: 27096305
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  • 3
    Abstract: Costimulatory ligands (COLs) and their receptors (COR) regulate immune reactions and cellular survival and might be relevant in acute myeloid leukemia (AML). This study evaluated the clinical relevance of 4-1BBL, glucocorticoid-induced TNFR-related protein (GITR) and ligand (GITRL), CD80, and CD86 in case of expression on AML blasts. 98 patients were evaluated at initial diagnosis. Immunophenotypically evaluated specific fluorescence index (SFI) levels of COR and COL on blasts were correlated with morphological, cytogenetic, and several prognostic parameters. Significantly higher COR expression was seen in monocytic versus non-monocytic AML subtypes; GITR, p=0.05; GITRL, p=0.005; CD86, p=0.001). Cut-off values for two COR and their ligands were evaluated: cases presenting with 4-1BB values above cut-off 1.2 SFI levels correlated (tendentially) significantly with a higher probability for disease-free survival (DFS, p=0.06) and a favorable HR of 0.2; p=0.04 for relapse. HR for death was also significantly lower in this group (0.12; p=0.04). In contrast, a lower probability for DFS and overall survival was seen in cases with 4-1BBL expression above 2.2 SFI levels (p=0.08 and p=0.09). In addition, multivariate analysis showed a significantly higher probability of death in this group (HR 10.3, p=0.04). Expression of CD80 and CD86 did not show significant prognostic relevance. On initial diagnosis, 4-1BB and 4-1BBL qualify as markers for prediction of patients' course and represent a valuable screening target for patients with AML at initial diagnosis.
    Type of Publication: Journal article published
    PubMed ID: 27388616
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