2. Academic Validation
  3. FLI1 regulates inflammation-associated genes to accelerate leukemogenesis

FLI1 regulates inflammation-associated genes to accelerate leukemogenesis

  • Cell Signal. 2022 Apr;92:110269. doi: 10.1016/j.cellsig.2022.110269.
Beiling Chen 1,  Danmei Sheng 1,  Chunlin Wang 1,  Wuling Liu 1,  Anling Hu 1,  Xiao Xiao 1,  Babu Gajendran 2,  Jian Gao 1,  Jifen Hu 1,  Klarke M Sample 1,  Eldad Zacksenhaus 3,  Yaacov Ben-David 4
Affiliations

Affiliations

  • 1 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, People's Republic of China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang 550014, Guizhou Province, People's Republic of China.
  • 2 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, People's Republic of China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang 550014, Guizhou Province, People's Republic of China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, People's Republic of China.
  • 3 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
  • 4 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, People's Republic of China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang 550014, Guizhou Province, People's Republic of China. Electronic address: yaacovbendavid@hotmail.com.
PMID: 35104574 DOI: 10.1016/j.cellsig.2022.110269
Abstract

Inflammation plays a critical role in Cancer initiation and progression, and is induced by inflammatory factors that are direct target of oncogenes and tumor suppressors. The ETS related transcription factor Fli-1 is involved in the induction and progression of various cancers; yet its role in inflammation is not well-defined. Using RNAseq analysis, we herein demonstrate that FLI1 induces the inflammatory pathway in erythroleukemia cells. Majority of genes within the TNF signaling pathway including TNF and IL1B were identified as transcriptional targets of FLI1. TNF expression is indirectly regulated by FLI1 through upregulation of another ETS related oncogene, SPI1/PU.1. Pharmacological inhibition of TNF significantly inhibited leukemia cell proliferation in culture. In contrast, IL1B expression is directly regulated by FLI1 through promoter binding and transcriptional activation. The secreted factor IL1B binds its canonical receptors to accelerate Cancer progression through changes in the surrounding tumor microenvironment, fostering cell survival, proliferation and migration. Through network analysis, we identified IL1B-interacting genes whose expression is also regulated by FLI1. Among these, IL1B-interacting proteins, FOS, JUN, JUNB and CASP1 are negatively regulated by FLI1. Treatment of leukemia cells with inhibitors of AP1 (TAN IIA) and CASP1 (765VX) significantly accelerated FLI1-dependent leukemia progression. These results emphasize the significance of FLI1 in regulating the inflammatory pathway. Targeting these inflammatory genes downstream of FLI1 offers a novel strategy to treat leukemic progression associated with overexpression of this oncogenic ETS transcription factor.

Keywords

Fli-1; IL1b; Inflammation genes; Leukemia progression; SPI1; TNF.

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