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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 ligand-dependent manner.
Blood 2004; 104(2):526-34Blood

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 G(alphai) proteins and require the mitogen-induced extracellular kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. Down-regulation of cyclic adenosine monophosphate (cAMP) levels upon G(alphai) 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 G(alphai) 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.

Authors+Show Affiliations

Erasmus MC, Department of Hematology, Dr Molewaterplein 50, 3015GE Rotterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15039279

Citation

Alberich Jordà, Meritxell, et al. "The Peripheral Cannabinoid Receptor Cb2, Frequently Expressed On AML Blasts, Either Induces a Neutrophilic Differentiation Block or Confers Abnormal Migration Properties in a Ligand-dependent Manner." Blood, vol. 104, no. 2, 2004, pp. 526-34.
Alberich Jordà M, Rayman N, Tas M, et al. The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood. 2004;104(2):526-34.
Alberich Jordà, M., Rayman, N., Tas, M., Verbakel, S. E., Battista, N., van Lom, K., ... Delwel, R. (2004). The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood, 104(2), pp. 526-34.
Alberich Jordà M, et al. The Peripheral Cannabinoid Receptor Cb2, Frequently Expressed On AML Blasts, Either Induces a Neutrophilic Differentiation Block or Confers Abnormal Migration Properties in a Ligand-dependent Manner. Blood. 2004 Jul 15;104(2):526-34. PubMed PMID: 15039279.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. AU - Alberich Jordà,Meritxell, AU - Rayman,Nazik, AU - Tas,Marjolein, AU - Verbakel,Sandra E, AU - Battista,Natalia, AU - van Lom,Kirsten, AU - Löwenberg,Bob, AU - Maccarrone,Mauro, AU - Delwel,Ruud, Y1 - 2004/03/23/ PY - 2004/3/25/pubmed PY - 2004/8/18/medline PY - 2004/3/25/entrez SP - 526 EP - 34 JF - Blood JO - Blood VL - 104 IS - 2 N2 - 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 G(alphai) proteins and require the mitogen-induced extracellular kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. Down-regulation of cyclic adenosine monophosphate (cAMP) levels upon G(alphai) 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 G(alphai) 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. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/15039279/The_peripheral_cannabinoid_receptor_Cb2_frequently_expressed_on_AML_blasts_either_induces_a_neutrophilic_differentiation_block_or_confers_abnormal_migration_properties_in_a_ligand_dependent_manner_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=15039279 DB - PRIME DP - Unbound Medicine ER -