Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

L. P. Song, J. Zhang, S. F. Wu, Y. Huang, Q. Zhao, J. P. Cao, Y. L. Wu, L. S. Wang, G. Q. Chen

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1α in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1α was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1α induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1α expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1Β, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-α (C/EBPα) significantly eliminated HIF-1α-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1α protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPα elicits a role as an effector downstream to HIF-1α. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.

Original languageEnglish (US)
Pages (from-to)519-527
Number of pages9
JournalOncogene
Volume27
Issue number4
DOIs
StatePublished - Jan 17 2008

Keywords

  • C/EBPα
  • Differentiation
  • HIF-1α
  • Leukemia

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Song, L. P., Zhang, J., Wu, S. F., Huang, Y., Zhao, Q., Cao, J. P., Wu, Y. L., Wang, L. S., & Chen, G. Q. (2008). Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent. Oncogene, 27(4), 519-527. https://doi.org/10.1038/sj.onc.1210670