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The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligang-dependent manner
- Source :
- Blood, 104, 526-534. American Society of Hematology
- Publication Year :
- 2004
-
Abstract
- Cb2, the gene encoding the peripheral cannabinoid receptor, is located in a common virus integration site and is overex-pressed in retrovirally induced murine myeloid leukemias. Here we show that this G protein-coupled receptor (GPCR) is also aberrantly expressed in a high percentage of human acute myeloid leukemias. We investigated the mechanism of transformation by Cb2 and demonstrate that aberrant expression of this receptor on hematopoietic precursor cells results in distinct effects depending on the ligand used. Cb2-expressing myeloid precursors migrate upon stimulation by the endocannabinoid 2-arachidonoylglycerol and are blocked in neutrophilic differentiation upon exposure to another ligand, CP55940. Both effects depend on the activation of Gαi proteins and require the mitogen-induced extracellular kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. Down-regulation of cyclic adenosine monophosphate (cAMP) levels upon Gαi activation is important for migration induction but is irrelevant for the maturation arrest. Moreover, the highly conserved G protein-interacting DRY motif, present in the second intracellular loop of GPCRs, is critical for migration but unimportant for the differentiation block. This suggests that the Cb2-mediated differentiation block requires interaction of Gαi proteins with other currently unknown motifs. This indicates a unique mechanism by which a transforming GPCR, in a ligand-dependent manner, causes 2 distinct oncogenic effects: altered migration and block of neutrophilic development. (Blood. 2004;104:526-534)
- Subjects :
- MAPK/ERK pathway
MAP Kinase Signaling System
Neutrophils
Immunology
Down-Regulation
Arachidonic Acids
Biology
Ligands
Biochemistry
Glycerides
Receptor, Cannabinoid, CB2
chemistry.chemical_compound
Cell Movement
Cannabinoid Receptor Modulators
Cyclic AMP
Extracellular
Humans
Cyclic adenosine monophosphate
Receptor
G protein-coupled receptor
Kinase
Cell Differentiation
Cell Biology
Hematology
Cyclohexanols
Hematopoietic Stem Cells
Endocannabinoid system
Cell biology
Bucladesine
Pertussis Toxin
chemistry
Leukemia, Myeloid
Acute Disease
Receptors, Granulocyte Colony-Stimulating Factor
Mutagenesis, Site-Directed
lipids (amino acids, peptides, and proteins)
Immunosuppressive Agents
Intracellular
Endocannabinoids
Subjects
Details
- ISSN :
- 00064971
- Database :
- OpenAIRE
- Journal :
- Blood, 104, 526-534. American Society of Hematology
- Accession number :
- edsair.doi.dedup.....34b96851416096aac62d442a7ef12d59