Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, 116027, China.
Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of hematology, Diamond Bay institute of hematology, Blood Stem Cell Transplantation Institute, the Second Hospital of Dalian Medical University, Dalian, 116027, China.
Cell Commun Signal. 2024 Apr 2;22(1):211. doi: 10.1186/s12964-024-01596-9.
The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.
EP300-ZNF384 融合基因是 B 细胞急性淋巴细胞白血病（B-ALL）的致癌驱动基因。在本研究中，我们证明 EP300-ZNF384 可大量诱导 B-ALL 细胞膜上 IL3RA 的转录和 IL3Rα（CD123）的表达。白细胞介素 3（IL-3）补充通过激活 STAT5 促进 EP300-ZNF384 阳性 B-ALL 细胞的增殖。在 EP300-ZNF384 阳性细胞中条件性敲低 IL3RA 可抑制体外增殖，并显著增加小鼠的总生存率，这归因于白血病细胞增殖能力受损。在机制上，EP300-ZNF384 融合蛋白通过结合位于 IL3RA-222/-234 的富含 A 的序列，反式激活 IL3RA 的启动子活性。此外，强制表达 EP300-ZNF384 可诱导健康个体来源的 CD19 阳性 B 前体细胞细胞膜上的 IL3Rα 表达和 IL-3 的分泌。阿霉素在体外和体内对 EP300-ZNF384 阳性 B-ALL 细胞具有选择性杀伤作用。总之，我们将 IL3RA 鉴定为 EP300-ZNF384 的直接下游靶标，表明 CD123 是 EP300-ZNF384 驱动的 B-ALL 的有效生物标志物。针对 CD123 可能是一种新的治疗方法，用于 EP300-ZNF384 阳性患者，可替代或更可能是在临床环境中补充标准化疗方案。
