2. Academic Validation
  3. EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia

EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia

  • Cell Commun Signal. 2024 Apr 2;22(1):211. doi: 10.1186/s12964-024-01596-9.
Zhijie Hou # 1 2 3 4,  Yifei Ren # 5 6 7,  Xuehong Zhang # 8,  Dan Huang 5 6 7,  Fanzhi Yan 5 6 7,  Wentao Sun 9,  Wenjuan Zhang 9,  Qingqing Zhang 10,  Xihui Fu 9,  Zhenghui Lang 9,  Chenyang Chu 9,  Boyang Zou 9,  Beibei Gao 5 6 7,  Bilian Jin 9,  Zhijie Kang 11 12 13,  Quentin Liu 14,  Jinsong Yan 15 16 17
Affiliations

Affiliations

  • 1 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, 116027, China. houzhijie_818@126.com.
  • 2 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. houzhijie_818@126.com.
  • 3 Department of Pediatric, Pediatric Oncology and Hematology Center, the Second Hospital of Dalian Medical University, Dalian, 116027, China. houzhijie_818@126.com.
  • 4 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, China. houzhijie_818@126.com.
  • 5 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, 116027, China.
  • 6 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.
  • 7 Department of Pediatric, Pediatric Oncology and Hematology Center, the Second Hospital of Dalian Medical University, Dalian, 116027, China.
  • 8 Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
  • 9 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, China.
  • 10 Department of Pathology, Dalian Medical University, Dalian, 116044, China.
  • 11 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, 116027, China. kangzhijie2013@163.com.
  • 12 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. kangzhijie2013@163.com.
  • 13 Department of Pediatric, Pediatric Oncology and Hematology Center, the Second Hospital of Dalian Medical University, Dalian, 116027, China. kangzhijie2013@163.com.
  • 14 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, China. liuq9@mail.sysu.edu.cn.
  • 15 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, 116027, China. yanjsdmu@dmu.edu.cn.
  • 16 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. yanjsdmu@dmu.edu.cn.
  • 17 Department of Pediatric, Pediatric Oncology and Hematology Center, the Second Hospital of Dalian Medical University, Dalian, 116027, China. yanjsdmu@dmu.edu.cn.
  • # Contributed equally.
PMID: 38566191 DOI: 10.1186/s12964-024-01596-9
Abstract

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.

Keywords

B-cell acute lymphoblastic leukemia; EP300-ZNF384; IL-3; IL3RA; Leukemogenesis.

Figures
Products
Inhibitors & Agonists