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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2034.
Submitted July 8, 2002
Accepted September 30, 2002
The peripheral cannabinoid receptor Cb2, a novel onco-protein, induces a reversible block in neutrophilic differentiation
Meritxell Alberich Jorda, Bob Lowenberg, and Ruud Delwel*
Institute for Hematology, Erasmus Medical Center, Rotterdam, The Netherlands
* Corresponding author; email: delwel{at}hema.fgg.eur.nl.
We previously identified a novel common virus integration site, Evi11, by means of retroviral insertional mutagenesis. We demonstrated that the gene encoding the peripheral cannabinoid receptor (Cb2) is the potential target, suggesting that Cb2 is a proto-oncogene. To elucidate a role for this G protein-coupled receptor (GPCR) in leukemic transformation we generated a Cb2-EGFP cDNA construct that was introduced into 32D/G-CSF-R cells. These cells require IL-3 to proliferate in vitro, whereas in the presence of G-CSF they differentiate towards mature neutrophils. We demonstrate that 32D/G-CSF-R/Cb2-EGFP cells migrate in a transwell assay in reponse to the Cb2 ligand 2-arachidonoylglycerol (2-AG), indicating that the fusion protein was functional. When cultured in the presence of G-CSF neutrophilic differentiation of Cb2-EGFP expressing 32D/G-CSF-R cells was completely blocked. Moreover, a Cb2-specific antagonist fully recovered the G-CSF-induced neutrophilic differentiation of 32D/G-CSF-R/Cb2-EGFP cells. To investigate which signal transduction pathway(s) may be involved in the block of neutrophilic maturation, differentiation experiments were carried out using specific inhibitors of signaling routes. Interestingly, full rescue of G-CSF induced neutrophilic differentiation was observed when cells were cultured with the MEK inhibitors, PD98059 or U0126, and partial recovery was detected with the PI3-K inhibitor LY-294,002. These studies demonstrate that the Cb2 receptor is an onco-protein that blocks neutrophilic differentiation when overexpressed in myeloid precursor cells. Cb2 appears to mediate its activity through MEK/ERK and PI3-K pathways.
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