Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells

Asish K. Ghosh, Tait D. Shanafelt, Amelia Cimmino, Cristian Taccioli, Stefano Volinia, Chang Gong Liu, George A. Calin, Carlo M. Croce, Denise A. Chan, Amato J. Giaccia, Charla Secreto, Linda E. Wellik, Yean K. Lee, Debabrata Mukhopadhyay, Neil E. Kay

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96 Scopus citations

Abstract

The molecular mechanism of autocrine regulation of vascular endothelial growth factor (VEGF) in chronic lymphocytic leukemia (CLL) B cells is unknown. Here, we report that CLL B cells express constitutive levels of HIF-1α under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1α degradation and found it to be at a notably low level in CLL B cells compared with normal B cells. We demonstrate that the microRNA, miR- 92-1, overexpressed in CLL B cells, can target the VHL transcript to repress its expression. We found that the stabilized HIF-1α can form an active complex with the transcriptional coactivator p300 and phosphorylated-STAT3 at the VEGF promoter and recruit RNA polymerase II. This is initial evidence that pVHL, without any genetic alteration, can be regulated by microRNA and explains the aberrant autocrine VEGF secretion in CLL.

Original languageEnglish (US)
Pages (from-to)5568-5574
Number of pages7
JournalBlood
Volume113
Issue number22
DOIs
StatePublished - Nov 19 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ghosh, A. K., Shanafelt, T. D., Cimmino, A., Taccioli, C., Volinia, S., Liu, C. G., Calin, G. A., Croce, C. M., Chan, D. A., Giaccia, A. J., Secreto, C., Wellik, L. E., Lee, Y. K., Mukhopadhyay, D., & Kay, N. E. (2009). Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood, 113(22), 5568-5574. https://doi.org/10.1182/blood-2008-10-185686