Faculty of Pharmacy, Centre Hospitalier Universitaire de Québec Research Center - Université Laval (CRCHUQc- UL), Université Laval, Québec, QC, Canada.
Cancer research center of Université Laval, Québec, Canada.
BMC Cancer. 2024 Apr 2;24(1):410. doi: 10.1186/s12885-024-12143-7.
High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key determinants driving expression of the UGT2B17 gene in normal and leukemic B-cells remain undefined. The UGT2B17 transcriptome is complex and is comprised of at least 10 alternative transcripts, identified by previous RNA-sequencing of liver and intestine. We hypothesized that the transcriptional program regulating UGT2B17 in B-lymphocytes is distinct from the canonical expression previously characterized in the liver.
RNA-sequencing and genomics data revealed a specific genomic landscape at the UGT2B17 locus in normal and leukemic B-cells. RNA-sequencing and quantitative PCR data indicated that the UGT2B17 enzyme is solely encoded by alternative transcripts expressed in CLL patient cells and not by the canonical transcript widely expressed in the liver and intestine. Chromatin accessible regions (ATAC-Seq) in CLL cells mapped with alternative promoters and non-coding exons, which may be derived from endogenous retrotransposon elements. By luciferase reporter assays, we identified key cis-regulatory STAT3, RELA and interferon regulatory factor (IRF) binding sequences driving the expression of UGT2B17 in lymphoblastoid and leukemic B-cells. Electrophoretic mobility shift assays and pharmacological inhibition demonstrated key roles for the CLL prosurvival transcription factors STAT3 and NF-κB in the leukemic expression of UGT2B17.
UGT2B17 expression in B-CLL is driven by key regulators of CLL progression. Our data suggest that a NF-κB/STAT3/IRF/UGT2B17 axis may represent a novel B-cell pathway promoting disease progression and drug resistance.
糖基转移酶 UGT2B17 的高表达代表慢性淋巴细胞白血病 (CLL) 的独立不良预后标志物。它也是治疗反应的预测标志物和耐药机制。在正常和白血病 B 细胞中驱动 UGT2B17 基因表达的关键决定因素尚不清楚。UGT2B17 的转录组是复杂的，至少由 10 种先前在肝脏和肠道的 RNA 测序中鉴定的替代转录本组成。我们假设调节 B 淋巴细胞中 UGT2B17 的转录程序与以前在肝脏中表征的典型表达不同。
RNA-seq 和基因组学数据揭示了正常和白血病 B 细胞中 UGT2B17 基因座的特定基因组图谱。RNA-seq 和定量 PCR 数据表明，UGT2B17 酶仅由 CLL 患者细胞中表达的替代转录本编码，而不是由广泛在肝脏和肠道表达的典型转录本编码。CLL 细胞中的染色质可及区域 (ATAC-Seq) 映射到替代启动子和非编码外显子，这些可能来自内源性逆转录转座子元件。通过荧光素酶报告基因测定，我们确定了关键的顺式调节 STAT3、RELA 和干扰素调节因子 (IRF) 结合序列，这些序列驱动淋巴母细胞和白血病 B 细胞中 UGT2B17 的表达。电泳迁移率变动分析和药理学抑制实验表明，CLL 生存转录因子 STAT3 和 NF-κB 在 UGT2B17 的白血病表达中起关键作用。
B-CLL 中的 UGT2B17 表达由 CLL 进展的关键调节剂驱动。我们的数据表明，NF-κB/STAT3/IRF/UGT2B17 轴可能代表一种新的 B 细胞途径，可促进疾病进展和耐药性。
