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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5568-5574.
Prepublished online as a Blood First Edition Paper on March 31, 2009; DOI 10.1182/blood-2008-10-185686.
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Submitted October 22, 2008
Accepted February 26, 2009
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, and Neil E. Kay*
Mayo Clinic College of Medicine, Rochester, MN, United States
Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
Department of Experimental Therapeutics and Cancer Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Radiation Oncology, Stanford University, Stanford, CA, United States
* Corresponding author; email: kay.neil{at}mayo.edu.
The molecular mechanism of autocrine regulation of VEGF in CLL B cells is unknown. Here, we report that CLL B cells express constitutive levels of HIF-1 under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1 degradation and found it to be at a notably low level in CLL B cells when 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-1 can form an active complex with the transcriptional co-activator 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.
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