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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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LYMPHOID NEOPLASIA

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

Asish K. Ghosh1, Tait D. Shanafelt1, Amelia Cimmino2, Cristian Taccioli2, Stefano Volinia2, Chang-gong Liu2, George A. Calin2,3, Carlo M. Croce2, Denise A. Chan4, Amato J. Giaccia4, Charla Secreto1, Linda E. Wellik1, Yean K. Lee1, Debabrata Mukhopadhyay1, and Neil E. Kay1

1 Mayo Clinic College of Medicine, Rochester, MN; 2 Comprehensive Cancer Center, The Ohio State University, Columbus; 3 Department of Experimental Therapeutics and Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston; and 4 Department of Radiation Oncology, Stanford University, CA

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-1{alpha} under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1{alpha} 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-1{alpha} 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.


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