Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation

Cancer Sci. 2021 Oct;112(10):4112-4126. doi: 10.1111/cas.15098. Epub 2021 Aug 22.

Abstract

Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.

Keywords: acute myeloid leukemia; gluconeogenesis; oncogene; pentose phosphate pathway; transcription factors.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Fructose-Bisphosphatase / antagonists & inhibitors
  • Fructose-Bisphosphatase / genetics
  • Fructose-Bisphosphatase / metabolism*
  • Gene Expression Profiling
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • MDS1 and EVI1 Complex Locus Protein / metabolism*
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Pentose Phosphate Pathway* / genetics
  • RNA, Small Interfering
  • Tumor Stem Cell Assay
  • Up-Regulation

Substances

  • MDS1 and EVI1 Complex Locus Protein
  • Mecom protein, mouse
  • RNA, Small Interfering
  • Fructose-Bisphosphatase