7 results on '"Kuil, Annemieke"'
Search Results
2. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients.
- Author
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Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, Kuil A, Herman SE, Chang S, Pals ST, Wilson W, Wiestner A, Spaargaren M, Buggy JJ, and Elias L
- Subjects
- Adenine analogs & derivatives, Antigens, CD19 biosynthesis, B-Lymphocytes metabolism, Blotting, Western, CD5 Antigens biosynthesis, Cell Adhesion drug effects, Flow Cytometry, Humans, Lymphoma, Mantle-Cell drug therapy, Piperidines, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, B-Lymphocytes drug effects, Chemotaxis, Leukocyte drug effects, Lymphoma, Mantle-Cell blood, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
- Published
- 2013
- Full Text
- View/download PDF
3. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.
- Author
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de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, and Spaargaren M
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Apoptosis drug effects, Blotting, Western, Cell Proliferation drug effects, Fibronectins metabolism, Flow Cytometry, Humans, Integrin alpha4beta1 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Piperidines, Protein-Tyrosine Kinases metabolism, RNA, Messenger genetics, Signal Transduction drug effects, Tumor Cells, Cultured, Vascular Cell Adhesion Molecule-1 metabolism, Cell Adhesion drug effects, Cell Movement drug effects, Chemokines metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrimidines pharmacology, Receptors, Antigen, B-Cell metabolism
- Abstract
Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
- Published
- 2012
- Full Text
- View/download PDF
4. Disruption of heparan sulfate proteoglycan conformation perturbs B-cell maturation and APRIL-mediated plasma cell survival.
- Author
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Reijmers RM, Groen RW, Kuil A, Weijer K, Kimberley FC, Medema JP, van Kuppevelt TH, Li JP, Spaargaren M, and Pals ST
- Subjects
- Animals, Carbohydrate Epimerases genetics, Cell Differentiation genetics, Cell Survival genetics, Cell Survival immunology, Heparan Sulfate Proteoglycans genetics, Heparan Sulfate Proteoglycans metabolism, Mice, Mice, Knockout, Plasma Cells enzymology, Signal Transduction genetics, Tumor Necrosis Factor Ligand Superfamily Member 13 genetics, Tumor Necrosis Factor Ligand Superfamily Member 13 metabolism, Carbohydrate Epimerases immunology, Cell Differentiation immunology, Heparan Sulfate Proteoglycans immunology, Plasma Cells immunology, Signal Transduction immunology, Tumor Necrosis Factor Ligand Superfamily Member 13 immunology
- Abstract
The development and antigen-dependent differentiation of B lymphocytes are orchestrated by an array of growth factors, cytokines, and chemokines that require tight spatiotemporal regulation. Heparan sulfate proteoglycans specifically bind and regulate the bioavailability of soluble protein ligands, but their role in the immune system has remained largely unexplored. Modification of heparan sulfate by glucuronyl C5-epimerase (Glce) controls heparan sulfate-chain flexibility and thereby affects ligand binding. Here we show that Glce deficiency impairs B-cell maturation, resulting in decreased plasma cell numbers and immunoglobulin levels. We demonstrate that C5-epimerase modification of heparan sulfate is critical for binding of a proliferation inducing ligand (APRIL) and that Glce-deficient plasma cells fail to respond to APRIL-mediated survival signals. Our results identify heparan sulfate proteoglycans as novel players in B-cell maturation and differentiation and suggest that heparan sulfate conformation is crucial for recruitment of factors that control plasma cell survival.
- Published
- 2011
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5. Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma.
- Author
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Reijmers RM, Groen RW, Rozemuller H, Kuil A, de Haan-Kramer A, Csikós T, Martens AC, Spaargaren M, and Pals ST
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, DNA-Binding Proteins genetics, Doxycycline administration & dosage, Drug Delivery Systems, Gene Targeting, Heparitin Sulfate metabolism, Humans, Immunoglobulin gamma-Chains genetics, Mice, Mice, Knockout, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, N-Acetylglucosaminyltransferases antagonists & inhibitors, N-Acetylglucosaminyltransferases physiology, Syndecan-1 genetics, Syndecan-1 metabolism, Xenograft Model Antitumor Assays, Cell Proliferation drug effects, Heparitin Sulfate physiology, Multiple Myeloma pathology, N-Acetylglucosaminyltransferases genetics, RNA, Small Interfering pharmacology
- Abstract
Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS side chains. Here, we show that inducible RNAi-mediated knockdown of syndecan-1 in human MM cells leads to reduced growth rates and a strong increase of apoptosis. Importantly, knockdown of EXT1, a copolymerase critical for HS chain biosynthesis, had similar effects. Using an innovative myeloma xenotransplantation model in Rag-2(-/-)gamma(c)(-/-) mice, we demonstrate that induction of EXT1 knockdown in vivo dramatically suppresses the growth of bone marrow localized myeloma. Our findings provide direct evidence that the HS chains of syndecan-1 are crucial for the growth and survival of MM cells within the bone marrow environment, and indicate the HS biosynthesis machinery as a potential treatment target in MM.
- Published
- 2010
- Full Text
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6. The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells.
- Author
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de Gorter DJ, Reijmers RM, Beuling EA, Naber HP, Kuil A, Kersten MJ, Pals ST, and Spaargaren M
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes pathology, Cell Line, Tumor, Chemokine CXCL12 pharmacology, Chickens, Enzyme Activation drug effects, Enzyme Activation genetics, Genes, Dominant genetics, Homeostasis drug effects, Homeostasis genetics, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Leukemia, Plasma Cell genetics, Leukemia, Plasma Cell pathology, Mutation, Oncogene Protein p21(ras) genetics, Oncogene Protein p21(ras) metabolism, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phospholipase C gamma genetics, Phospholipase C gamma metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Syk Kinase, ral GTP-Binding Proteins genetics, src-Family Kinases genetics, src-Family Kinases metabolism, B-Lymphocytes metabolism, Cell Movement drug effects, Cell Movement genetics, Chemokine CXCL12 metabolism, Leukemia, Plasma Cell metabolism, ral GTP-Binding Proteins metabolism
- Abstract
Chemokine-controlled migration plays a critical role in B-cell development, differentiation, and function, as well as in the pathogenesis of B-cell malignancies, including the plasma cell neoplasm multiple myeloma (MM). Here, we demonstrate that stimulation of B cells and MM cells with the chemokine stromal cell-derived factor-1 (SDF-1) induces strong migration and activation of the Ras-like GTPase Ral. Inhibition of Ral, by expression of the dominant negative RalN28 mutant or of RalBPDeltaGAP, a Ral effector mutant that sequesters active Ral, results in impaired SDF-1-induced migration of B cells and MM cells. Of the 2 Ral isoforms, RalA and RalB, RalB was found to mediate SDF-1-induced migration. We have recently shown that Btk, PLCgamma2, and Lyn/Syk mediate SDF-1-controlled B-cell migration; however, SDF-1-induced Ral activation is not affected in B cells deficient in these proteins. In addition, treatment with pharmacological inhibitors against PI3K and PLC or expression of dominant-negative Ras did not impair SDF-1-induced Ral activation. Taken together, these results reveal a novel function for Ral, that is, regulation of SDF-1-induced migration of B cells and MM cells, thereby providing new insights into the control of B-cell homeostasis, trafficking, and function, as well as into the pathogenesis of MM.
- Published
- 2008
- Full Text
- View/download PDF
7. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides.
- Author
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Zelcer N, van de Wetering K, de Waart R, Scheffer GL, Marschall HU, Wielinga PR, Kuil A, Kunne C, Smith A, van der Valk M, Wijnholds J, Elferink RO, and Borst P
- Subjects
- Animals, Bile Ducts physiopathology, Bilirubin analogs & derivatives, Bilirubin blood, Biological Transport genetics, Biological Transport physiology, Cholic Acids metabolism, Deoxycholic Acid metabolism, Ileum metabolism, Immunoblotting, Immunohistochemistry, Ligation, Liver chemistry, Male, Mice, Mice, Inbred Strains, Multidrug Resistance-Associated Proteins analysis, Multidrug Resistance-Associated Proteins genetics, Taurocholic Acid metabolism, Bile Acids and Salts metabolism, Glucuronides metabolism, Liver metabolism, Multidrug Resistance-Associated Proteins deficiency, Multidrug Resistance-Associated Proteins physiology
- Abstract
Background/aim: Multidrug Resistance Protein 3 (MRP3) transports bile salts and glucuronide conjugates in vitro and is postulated to protect the liver in cholestasis. Whether the absence of Mrp3 affects these processes in vivo is tested., Methods: Mrp3-deficient mice were generated and the contribution of Mrp3 to bile salt and glucuronide conjugate transport was tested in (1): an Ussing-chamber set-up with ileal explants (2), the liver during bile-duct ligation (3), liver perfusion experiments, and (4) in vitro vesicular uptake experiments., Results: The Mrp3((-/-)) mice show no overt phenotype. No differences between WT and Mrp3-deficient mice were found in the trans-ileal transport of taurocholate. After bile-duct ligation, there were no differences in histological liver damage and serum bile salt levels between Mrp3((-/-)) and WT mice, but Mrp3-deficient mice had lower serum bilirubin glucuronide concentrations. Glucuronide conjugates of hyocholate and hyodeoxycholate are substrates of MRP3 in vitro and in livers that lack Mrp3, there is reduced sinusoidal secretion of hyodeoxycholate-glucuronide after perfusion with hyodeoxycholate., Conclusions: Mrp3 does not have a major role in bile salt physiology, but is involved in the transport of glucuronidated compounds, which could include glucuronidated bile salts in humans.
- Published
- 2006
- Full Text
- View/download PDF
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