Page 78 - Haematologica Vol. 109 - July 2024

ARTICLE - Acute Myeloid Leukemia
Targeting TNF/IL-17/MAPK pathway in hE2A-PBX1
leukemia: effects of OUL35, KJ-Pyr-9, and CID44216842
Haiping Luo,1* Qiqi Li,1* Jiaxin Hong,1 Zhibin Huang,1 Wenhui Deng,1 Kunpeng Wei,1 Siyu Lu,1 Hailong Wang,2 Wenqing Zhang1 and Wei Liu1
1Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology and 2KingMed School of Laboratory Medicine, Guangzhou Medical University, Department of Basic Research, Guangzhou Laboratory, Guangzhou, China
*HL and QL contributed equally as first authors.
Abstract
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-bind- ing 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 de- veloped. To address this, we established a stable and heritable zebrafish line expressing human E2A-PBX1 (hE2A-PBX1) for high-throughput drug screening. Blood phenotype analysis showed that hE2A-PBX1 expression induced myeloid hyperplasia by increasing myeloid differentiation propensity of hematopoietic stem cells (HSPC) 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 runx1. Interestingly, through high-through- put 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.
Correspondence: W. Liu liuwei7@scut.edu.cn
W. Zhang
mczhangwq@scut.edu.cn
Received: Accepted: Early view:
June 13, 2023. February 12, 2024. February 22, 2024.
https://doi.org/10.3324/haematol.2023.283647
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
t(1;19)(q23;p13) is the most common chromosomal trans- location in leukemia, causing 5-7% of childhood ALL1,2 and also AML/MPAL.3,4 In ALL, E2A-PBX1 is not a primary ALL prognostic factor, but it is associated with poor response to therapy and short remission.5 ALL patients with E2A-PBX1 translocation appear to have a high risk of relapse, and this translocation is also associated with known high-risk clinical features, including elevated white blood cell counts at diagnosis and central nervous system leukemia.6,7 Furthermore, a previous study has shown that the E2A-PBX1 fusion gene can serve as an effective minimal residual disease (MRD) marker follow- ing induction chemotherapy, the relapse rate of patients with rapid early conversion to negative for this gene is relatively low.5,8 Reports based on sporadic cases have indicated that E2A-PBX1-positive patients also exhibit
high-risk clinical features, including high cell counts, high serum lactate dehydrogenase levels, and central nervous system (CNS) involvement.3 Although recent intensified treatment regimens and allogeneic hematopoietic stem cell transplantation have improved the prognosis of adult ALL patients with E2A-PBX1,9 its systemic toxicity and high cost should not be overlooked.
The E2A-PBX1 protein resulting from t(1;19)(q23;p13) fusion combines the N-terminal transactivation domain of E2A (also known as TCF3) and the C-terminal DNA-binding homologous domain of PBX1.10 As a major regulator of B-lymphocyte generation, E2A determines the differen- tiation of B-cell lineages,11 also plays an important role in maintaining the hematopoietic stem cell pool and promoting the maturation of myelo-lymphoid and my- elo-erythroid progenitors.12 PBX1, a TALE (3-amino-acid loop extension) transcription factor, interacts with other members of the HOX family to enhance their DNA-binding
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