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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2034.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1336-1343
HEMATOPOIESIS
The peripheral cannabinoid receptor Cb2, a novel oncoprotein,
induces a reversible block in neutrophilic
differentiation
Meritxell Alberich Jordà,
Bob Löwenberg, and
Ruud Delwel
From The Institute for Hematology, Erasmus Medical
Center, The Netherlands.
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 interleukin
3 (IL-3) to proliferate in vitro, whereas in the presence of
granulocyte-colony-stimulating factor (G-CSF) they differentiate
toward 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
mitogen-induced extracellular kinase (MEK) inhibitors, PD98059 or
U0126, and partial recovery was detected with the phosphoinositide 3-kinase (PI3-K) inhibitor LY-294002. These studies demonstrate that
the Cb2 receptor is an oncoprotein that blocks neutrophilic differentiation when overexpressed in myeloid precursor cells. Cb2
appears to mediate its activity through MEK/extracellular signal-related kinase (ERK) and PI3-K pathways.
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