Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high risk chronic lymphocytic leukemia

Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P = .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P = .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications

European Journal of Nuclear Medicine and Molecular Imaging / Ultra-early response assessment in lymphoma treatment : [18F]FDG PET/MR captures changes in glucose metabolism and cell density within the first 72 hours of treatment

Purpose To determine whether, in patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), [18F]FDG PET/MR can capture treatment effects within the first week after treatment initiation, and whether changes in glucose metabolism and cell density occur simultaneously. Methods Patients with histologically proven HL or NHL were included in this prospective IRB-approved study. Patients underwent [18F]FDG PET/MR before, and then 4872 h after (follow-up 1, FU-1) and 1 week after (FU-2) initiation of the first cycle of their respective standard chemotherapy (for HL) or immunochemotherapy (for NHL). Standardized [18F]FDG uptake values (SUVmax, SUVmean) and apparent diffusion coefficients (ADCmin, ADCmean) based on diffusion-weighted MRI, and metabolic and morphological tumour volumes (MTV, VOL) were assessed at each time-point. Multilevel analyses with an unstructured covariance matrix, and pair-wise post-hoc tests were used to test for significant changes in SUVs, ADCs, MTVs and VOLs between the three time-points. Results A total of 58 patients (11 with HL and 47 with NHL) with 166 lesions were analysed. Lesion-based mean rates of change in SUVmax, SUVmean, ADCmin, ADCmean, MTV and VOL between baseline and FU-1 were 46.8%, 33.3%, +20.3%, +14%, 46% and 12.8%, respectively, and between baseline and FU-2 were 65.1%, 49%, +50.7%, +32.4%, 61.1% and 24.2%, respectively. These changes were statistically significant (P<0.01) except for the change in VOL between baseline and FU-1 (P=0.079). Conclusion In lymphoma patients, [18F]FDG PET/MR can capture treatment-induced changes in glucose metabolism and cell density as early as 4872 h after treatment initiation.(VLID)357846

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

ISSN:1552-4450ISSN:1552-446