Oncogenic FLT3 internal tandem duplication activates E2F1 to regulate purine metabolism in acute myeloid leukaemia

Zi-Yao Ou; Ke Wang; Wen-Wen Shen; Ge Deng; Ya-Yun Xu; Long-Fei Wang; Zhuo-Yan Zai; Yi-An Ling; Tao Zhang; Xiao-Qing Peng; Fei-Hu Chen

doi:10.1016/j.bcp.2023.115458

Oncogenic FLT3 internal tandem duplication activates E2F1 to regulate purine metabolism in acute myeloid leukaemia

Biochem Pharmacol. 2023 Apr:210:115458. doi: 10.1016/j.bcp.2023.115458. Epub 2023 Feb 17.

Authors

Zi-Yao Ou¹, Ke Wang², Wen-Wen Shen¹, Ge Deng¹, Ya-Yun Xu¹, Long-Fei Wang¹, Zhuo-Yan Zai¹, Yi-An Ling¹, Tao Zhang¹, Xiao-Qing Peng³, Fei-Hu Chen⁴

Affiliations

¹ School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
² Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China.
³ Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. Electronic address: pengxiaoqing@ahmu.edu.cn.
⁴ School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China. Electronic address: chenfeihu@ahmu.edu.cn.

PMID: 36803956
DOI: 10.1016/j.bcp.2023.115458

Abstract

Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD⁺ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-Prkdc^scidIl2rg^em1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34⁺ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD⁺ AML patients.

Keywords: AML; Purine metabolism; Targeted therapy; Transcription factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD34
Cells, Cultured
E2F1 Transcription Factor / genetics
Humans
Leukemia, Myeloid, Acute* / metabolism
Mice
Mice, Inbred NOD
Mutation
Purines
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antigens, CD34
Purines
fms-Like Tyrosine Kinase 3
FLT3 protein, human
E2F1 protein, human
E2F1 Transcription Factor