http://repub.eur.nl/res/aut/12339/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/32090/ 2011-09-23T00:00:00Z Non-Hodgkin’s lymphoma’s (NHLs) are a heterogeneous group of hematological malignancies with a large variation in clinical presentation, morphological appearance and prognosis. The NHLs make up the largest group (40-50%) of all hematological malignancies. In 2007, 17.700 people in the Netherlands had a non-Hodgkin’s lymphoma. Of these cases, 1.2/1000 was male and 1.2/1000 was female. The number of newly diagnosed NHL was 2800. In the same year, 1061 succumbed to the disease (585 male, 476 female)1. NHLs almost always arise from cells of the immune system resulting, in either B-cell or T-cell lymphomas. Most (approximately 85%) NHLs arise from their normal B-cell counterparts whereas a minority (approximately 15%) is derived from T-cells. Of the NHLs, approximately 65% arise in lymph nodes (nodal type), whereas the remaining 35% can arise in any organ (extra-nodal type). The most recent WHO classifi cation contains about 50 different (clinico-pathological) entities. Each entity is considered to have a normal physiological counterpart refl ecting the various differentiation stages in the lymphoid organs or bone marrow. http://repub.eur.nl/res/pub/8184/ 2004-01-01T00:00:00Z 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.