2. Academic Validation
  3. FLI1 accelerates leukemogenesis through transcriptional regulation of pyruvate kinase-L/R and other glycolytic genes

FLI1 accelerates leukemogenesis through transcriptional regulation of pyruvate kinase-L/R and other glycolytic genes

  • Med Oncol. 2022 Dec 31;40(2):69. doi: 10.1007/s12032-022-01867-w.
Danmei Sheng # 1 2,  Beiling Chen # 1 2,  Chunlin Wang # 1 2,  Xiao Xiao 1 2,  Anling Hu 1 2,  Wuling Liu 1 2,  Yi Kuang 1 2,  Klarke M Sample 3,  Eldad Zacksenhaus 4 5,  Babu Gajendran 6 7 8,  Weidong Pan 9 10,  Yaacov Ben-David 11 12
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.
  • 2 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.
  • 3 Institute of Life Science, eBond Pharmaceutical Technology Ltd., Chengdu, People's Republic of China.
  • 4 Department of Medicine, University of Toronto, Toronto, ON, Canada.
  • 5 Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
  • 6 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China. [email protected].
  • 7 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. [email protected].
  • 8 School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou Province, People's Republic of China. [email protected].
  • 9 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China. [email protected].
  • 10 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. [email protected].
  • 11 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China. [email protected].
  • 12 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. [email protected].
  • # Contributed equally.
PMID: 36586017 DOI: 10.1007/s12032-022-01867-w
Abstract

In Cancer cells, multiple oncogenes and tumor suppressors control glycolysis to sustain rapid proliferation. The ETS-related transcription factor Fli1 plays a critical role in the induction and progression of leukemia, yet, the underlying mechanism of this oncogenic event is still not fully understood. In this study, RNAseq analysis of FLI1-depleted human leukemic cells revealed transcriptional suppression of the PKLR gene and activation of multiple glycolytic genes, such as PKM1/2. Pharmacological inhibition of glycolysis by PKM2 inhibitor, Shikonin, significantly suppressed leukemic cell proliferation. FLI1 directly binds to the PKLR promoter, leading to the suppression of this inhibitor of glycolysis. In accordance, shRNA-mediated depletion of PKLR in leukemic HEL cells expressing high levels of FLI1 accelerated leukemia proliferation, pointing for the first time to its tumor suppressor function. PKLR knockdown also led to downregulation of the erythroid markers EPOR, HBA1, and HBA2 and suppression of erythroid differentiation. Interestingly, silencing of PKLR in HEL cells significantly increased FLI1 expression, which was associated with faster proliferation in culture. In FLI1-expressing leukemic cells, lower PKLR expression was associated with higher expression of PKM1 and PKM2, which promote aerobic glycolysis. Finally, injection of pyruvate, a known inhibitor of glycolysis, into leukemia mice significantly suppressed leukemogenesis. These results demonstrate that FLI1 promotes leukemia in part by inducing glycolysis, implicates PKLR in erythroid differentiation, and suggests that targeting glycolysis may be an attractive therapeutic strategy for cancers driven by FLI1 overexpression.

Keywords

Erythroid differentiation; FLI1; Lactic acid; Leukemia progression; PKLR; Pyruvate.

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