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

Meritxell Alberich Jordà, Nazik Rayman, Marjolein Tas, Sandra E. Verbakel, Natalia Battista, Kirsten Van Lom, Bob Löwenberg, Mauro Maccarrone, Ruud Delwel

Research output: Contribution to journalArticlepeer-review

Abstract

Cb2, the gene encoding the peripheral cannabinoid receptor, is located in a common virus integration site and is overexpressed 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.

Original languageEnglish
Pages (from-to)526-534
Number of pages9
JournalBlood
Volume104
Issue number2
DOIs
Publication statusPublished - Jul 15 2004

ASJC Scopus subject areas

  • Hematology

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