PMID- 38385270
OWN - NLM
STAT- Publisher
LR  - 20240222
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Linking)
DP  - 2024 Feb 22
TI  - Targeting TNF/IL-17/MAPK pathway in hE2A-PBX1 leukemia: effects of OUL35, 
      KJ-Pyr-9, and CID44216842.
LID - 10.3324/haematol.2023.283647 [doi]
AB  - t(1;19)(q23;p13) is one of the most common translocation genes in childhood acute 
      lymphoblastic leukemia (ALL) and is also present in acute myeloid leukemia (AML) 
      and mixed-phenotype acute leukemia (MPAL). This translocation results in the 
      formation of the oncogenic E2A-PBX1 fusion protein, which contains a 
      trans-activating domain from E2A and a DNA-binding homologous domain from PBX1. 
      Despite its clear oncogenic potential, the pathogenesis of E2A-PBX1 fusion 
      protein is not fully understood (especially in leukemias other than ALL), and 
      effective targeted clinical therapies have not been developed. To address this, 
      we established a stable and heritable zebrafish line expressing human E2A-PBX1 
      (hE2APBX1) for high-throughput drug screening. Blood phenotype analysis showed 
      that hE2APBX1 expression induced myeloid hyperplasia by increasing myeloid 
      differentiation propensity of hematopoietic stem cells (HSPCs) and myeloid 
      proliferation in larvae, and progressed to AML in adults. Mechanistic studies 
      revealed that hE2A-PBX1 activated the TNF/IL-17/MAPK signaling pathway in blood 
      cells and induced myeloid hyperplasia by upregulating the expression of the 
      runx1. Interestingly, through high-throughput drug screening, three small 
      molecules targeting the TNF/IL-17/MAPK signaling pathway were identified, 
      including OUL35, KJ-Pyr-9, and CID44216842, which not only alleviated the 
      hE2A-PBX1- induced myeloid hyperplasia in zebrafish but also inhibited the growth 
      and oncogenicity of human pre-B ALL cells with E2A-PBX1. Overall, this study 
      provides a novel hE2A-PBX1 transgenic zebrafish leukemia model and identifies 
      potential targeted therapeutic drugs, which may offer new insights into the 
      treatment of E2A-PBX1 leukemia.
FAU - Luo, Haiping
AU  - Luo H
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Li, Qiqi
AU  - Li Q
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Hong, Jiaxin
AU  - Hong J
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Huang, Zhibin
AU  - Huang Z
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Deng, Wenhui
AU  - Deng W
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Wei, Kunpeng
AU  - Wei K
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Lu, Siyu
AU  - Lu S
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006.
FAU - Wang, Hailong
AU  - Wang H
AD  - KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 
      China; Department of Basic Research, Guangzhou Laboratory, Guangzhou 510320.
FAU - Zhang, Wenqing
AU  - Zhang W
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006. mczhangwq@scut.edu.cn.
FAU - Liu, Wei
AU  - Liu W
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou 510006. liuwei7@scut.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20240222
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
SB  - IM
EDAT- 2024/02/22 06:43
MHDA- 2024/02/22 06:43
CRDT- 2024/02/22 05:37
PHST- 2023/06/13 00:00 [received]
PHST- 2024/02/22 06:43 [medline]
PHST- 2024/02/22 06:43 [pubmed]
PHST- 2024/02/22 05:37 [entrez]
AID - 10.3324/haematol.2023.283647 [doi]
PST - aheadofprint
SO  - Haematologica. 2024 Feb 22. doi: 10.3324/haematol.2023.283647.