Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells.
Ghosh AK., Shanafelt TD., Cimmino A., Taccioli C., Volinia S., Liu C-G., Calin GA., Croce CM., Chan DA., Giaccia AJ., Secreto C., Wellik LE., Lee YK., Mukhopadhyay D., Kay NE.
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-1alpha under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1alpha 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-1alpha 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.