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1.
J Exp Med ; 192(8): 1115-24, 2000 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-11034601

RESUMO

Recently, biochemical, cell biological, and genetic studies have converged to reveal that integral membrane heparan sulfate proteoglycans (HSPGs) are critical regulators of growth and differentiation of epithelial and connective tissues. As a large number of cytokines involved in lymphoid tissue homeostasis or inflammation contain potential HS-binding domains, HSPGs presumably also play important roles in the regulation of the immune response. In this report, we explored the expression, regulation, and function of HSPGs on B lymphocytes. We demonstrate that activation of the B cell antigen receptor (BCR) and/or CD40 induces a strong transient expression of HSPGs on human tonsillar B cells. By means of these HSPGs, the activated B cells can bind hepatocyte growth factor (HGF), a cytokine that regulates integrin-mediated B cell adhesion and migration. This interaction with HGF is highly selective since the HSPGs did not bind the chemokine stromal cell-derived factor (SDF)-1 alpha, even though the affinities of HGF and SDF-1alpha for heparin are similar. On the activated B cells, we observed induction of a specific HSPG isoform of CD44 (CD44-HS), but not of other HSPGs such as syndecans or glypican-1. Interestingly, the expression of CD44-HS on B cells strongly promotes HGF-induced signaling, resulting in an HS-dependent enhanced phosphorylation of Met, the receptor tyrosine kinase for HGF, as well as downstream signaling molecules including Grb2-associated binder 1 (Gab1) and Akt/protein kinase B (PKB). Our results demonstrate that the BCR and CD40 control the expression of HSPGs, specifically CD44-HS. These HSPGs act as functional coreceptors that selectively promote cytokine signaling in B cells, suggesting a dynamic role for HSPGs in antigen-specific B cell differentiation.


Assuntos
Linfócitos B/fisiologia , Antígenos CD40/fisiologia , Citocinas/fisiologia , Proteoglicanas de Heparan Sulfato/biossíntese , Receptores de Antígenos de Linfócitos B/imunologia , Linfócitos B/imunologia , Linfoma de Burkitt , Células Cultivadas , Quimiocina CXCL12 , Quimiocinas CXC/farmacocinética , Quimiocinas CXC/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/fisiologia , Cinética , Tonsila Palatina/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Estromais/fisiologia , Transfecção , Células Tumorais Cultivadas
2.
Leukemia ; 21(2): 215-21, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17170730

RESUMO

Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.


Assuntos
Genes de Imunoglobulinas , Leucemia de Células T/genética , Linfoma de Células T/genética , Reação em Cadeia da Polimerase/métodos , Receptores de Antígenos de Linfócitos T/genética , Amplificação de Genes , Rearranjo Gênico , Genótipo , Humanos , Imuno-Histoquímica , Leucemia Prolinfocítica/genética , Leucemia Prolinfocítica/imunologia , Leucemia Prolinfocítica/patologia , Leucemia de Células T/imunologia , Leucemia de Células T/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Linfócitos T/imunologia
3.
Leukemia ; 21(2): 207-14, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17170731

RESUMO

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.


Assuntos
Genes de Imunoglobulinas , Leucemia de Células B/genética , Linfoma de Células B/genética , Reação em Cadeia da Polimerase/métodos , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Rearranjo Gênico , Genótipo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia de Células B/diagnóstico , Leucemia de Células B/imunologia , Linfoma de Células B/diagnóstico , Linfoma de Células B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Translocação Genética
4.
Mol Biol Cell ; 10(10): 3239-50, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10512863

RESUMO

Rab5 is a regulatory GTPase of vesicle docking and fusion that is involved in receptor-mediated endocytosis and pinocytosis. Introduction of active Rab5 in cells stimulates the rate of endocytosis and vesicle fusion, resulting in the formation of large endocytic vesicles, whereas dominant negative Rab5 inhibits vesicle fusion. Here we show that introduction of active Rab5 in fibroblasts also induced reorganization of the actin cytoskeleton but not of microtubule filaments, resulting in prominent lamellipodia formation. The Rab5-induced lamellipodia formation did not require activation of PI3-K or the GTPases Ras, Rac, Cdc42, or Rho, which are all strongly implicated in cytoskeletal reorganization. Furthermore, lamellipodia formation by insulin, Ras, or Rac was not affected by expression of dominant negative Rab5. In addition, cells expressing active Rab5 displayed a dramatic stimulation of cell migration, with the lamellipodia serving as the leading edge. Both lamellipodia formation and cell migration were dependent on actin polymerization but not on microtubules. These results demonstrate that Rab5 induces lamellipodia formation and cell migration and that the Rab5-induced lamellipodia formation occurs by a novel mechanism independent of, and distinct from, PI3-K, Ras, or Rho-family GTPases. Thus, Rab5 can control not only endocytosis but also actin cytoskeleton reorganization and cell migration, which provides strong support for an intricate relationship between these processes.


Assuntos
Movimento Celular/efeitos dos fármacos , Proteínas rab5 de Ligação ao GTP/farmacologia , Células 3T3 , Actinas/metabolismo , Animais , Adesão Celular/genética , Movimento Celular/genética , Citoesqueleto/metabolismo , Endocitose/genética , Imunofluorescência , Genes ras , Humanos , Insulina/farmacologia , Fusão de Membrana/genética , Camundongos , Microscopia de Vídeo , Fosfatidilinositol 3-Quinases/genética , Transfecção , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/análise
5.
Oncogene ; 36(15): 2105-2115, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27775078

RESUMO

Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/ß-catenin signaling and loss of CYLD sensitizes MM cells to NF-κB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFκB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF-κB and Wnt/ß-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity.


Assuntos
Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas Supressoras de Tumor/deficiência , Via de Sinalização Wnt , Estudos de Casos e Controles , Enzima Desubiquitinante CYLD , Humanos , Mieloma Múltiplo/genética , NF-kappa B/metabolismo , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
Cell Death Differ ; 12(6): 637-48, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15846369

RESUMO

APRIL, a proliferation-inducing ligand, is a member of the tumor necrosis factor (TNF) family that is expressed by various types of tumors and influences their growth in vitro and in vivo. Two receptors, transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), bind APRIL, but neither is essential for the tumor-promoting effects, suggesting that a third receptor exists. Here, we report that APRIL specifically binds to heparan sulfate proteoglycans (HSPG) on the surface of tumor cells. This binding is mediated by the heparin sulfate side chains and can be inhibited by heparin. Importantly, BCMA and HSPG do not compete, but can bind APRIL simultaneously, suggesting that different regions in APRIL are critical for either interaction. In agreement, mutation of three lysines in a putative heparin sulfate-binding motif, which is not part of the TNF fold, destroys interaction with HSPG, while binding to BCMA is unaffected. Finally, whereas interaction of APRIL with HSPG does not influence APRIL-induced proliferation of T cells, it is crucial for its tumor growth-promoting activities. We therefore conclude that either HSPG serve as a receptor for APRIL or that HSPG binding allows APRIL to interact with a receptor that promotes tumor growth.


Assuntos
Proteoglicanas de Heparan Sulfato/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Necrose Tumoral alfa/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Proliferação de Células , Chlorocebus aethiops , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Mutação/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/genética
7.
Leukemia ; 30(2): 337-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26338274

RESUMO

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Antígenos CD40/fisiologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Pessoa de Meia-Idade , Purinas/farmacologia , Quinazolinonas/farmacologia , Linfócitos T/imunologia
8.
Oncogene ; 18(36): 5126-30, 1999 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-10490850

RESUMO

Granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5 belong to a family of cytokines that regulate proliferation, differentiation and function of haematopoietic cells. Their receptor consists of a ligand specific alpha-chain and a signal transducing beta-chain (betac). While, the role of phosphotyrosine residues in the betac as mediators of downstream signalling cascades has been established, little is known about non-phosphotyrosine mediated events. To identify proteins interacting with betac, we screened a yeast two-hybrid library with the intracellular domain of betac. We found that RACK1, a molecule associating with activated PKC, PLCgamma and Src kinases, associated with the membrane proximal region of betac in both yeast two-hybrid, immunoprecipitation and GST-pull-down assays. The association of RACK1 was constitutive, demonstrating no alteration upon cellular stimulation. Furthermore, upon stimulation of cells with IL-5 or PMA, a complex of betac and PKCbeta was found. Together, these findings suggest a novel role for RACK1 as a possible adapter molecule associating with the intracellular domain of cytokine receptors.


Assuntos
Isoenzimas/metabolismo , Peptídeos/metabolismo , Proteína Quinase C/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Interleucina-3/metabolismo , Receptores de Interleucina/metabolismo , Animais , Sequência de Bases , Células COS , DNA , Ligação Proteica , Proteína Quinase C beta , Receptores de Quinase C Ativada , Receptores de Interleucina-5
9.
Oncogene ; 13(2): 353-62, 1996 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-8710374

RESUMO

The small GTPase Rap 1A is a close relative of Ras that, when overexpressed, is able to revert oncogenic transformation induced by active Ras. We screened a mouse embryonic cDNA library using the yeast two-hybrid system and isolated the cDNA of a novel Rap 1A-interacting protein. The open reading frame encodes for an 84 kDa protein with a Cdc25-homology domain which shares approximately 30% identity with Ral guanine nucleotide dissociation stimulator (RalGDS) and RalGDS-like (Rg1). The C-terminal region reveals a striking conservation of sequences with the Ras-binding domain of RalGDS. We designated this protein Rlf, for RalGDS-like factor. In the yeast system, Rlf interacts with Rap 1A, H-Ras and R-Ras, but not with Rac and Rho. In addition, we found that Rlf interacts with Rap 1Aval12 but not with Rap 1AAsn17. In vitro binding studies revealed that a C-terminally located 91 amino acid region of Rlf is sufficient for direct association with the GTP-bound form of Ras and Rap 1A. The observed dissociation constants are 0.6 microM and 0.4 microM, respectively. No significant association with Ras-GDP or Rap 1A-GDP could be detected. These binding characteristics indicate that Rlf is a putative effector for Ras and Rap 1A.


Assuntos
DNA Complementar/genética , DNA Complementar/isolamento & purificação , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/isolamento & purificação , Fatores de Troca do Nucleotídeo Guanina , Fatores de Transcrição/genética , Fatores de Transcrição/isolamento & purificação , Proteínas ras/genética , Proteínas ras/isolamento & purificação , ras-GRF1 , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Clonagem Molecular , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Guanosina Trifosfato/metabolismo , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/metabolismo , Fator ral de Troca do Nucleotídeo Guanina , Proteínas rap de Ligação ao GTP , Proteínas ras/metabolismo
10.
Adv Cancer Res ; 79: 39-90, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10818677
11.
Leukemia ; 17(4): 764-74, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12682635

RESUMO

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.


Assuntos
Fator de Crescimento de Hepatócito/fisiologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/fisiologia , Proteínas Proto-Oncogênicas c-met/fisiologia , Idoso , Apoptose/fisiologia , Divisão Celular/fisiologia , Feminino , Humanos , MAP Quinase Quinase 1 , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , Plasmócitos/metabolismo , Plasmócitos/patologia , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/patologia , Proteínas ras/fisiologia
12.
Leukemia ; 17(12): 2257-317, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14671650

RESUMO

In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 multiplex PCR tubes: three VH-JH, two DH-JH, two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), one TCR delta (TCRD), three BCL1-Ig heavy chain (IGH), and one BCL2-IGH. The PCR products of Ig/TCR genes can be analyzed for clonality assessment by heteroduplex analysis or GeneScanning. The detection rate of clonal rearrangements using the BIOMED-2 primer sets is unprecedentedly high. This is mainly based on the complementarity of the various BIOMED-2 tubes. In particular, combined application of IGH (VH-JH and DH-JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations. The contribution of IGL gene rearrangements seems limited. Combined usage of the TCRB and TCRG tubes detects virtually all clonal T-cell populations, whereas the TCRD tube has added value in case of TCRgammadelta(+) T-cell proliferations. The BIOMED-2 multiplex tubes can now be used for diagnostic clonality studies as well as for the identification of PCR targets suitable for the detection of minimal residual disease.


Assuntos
Imunoglobulinas/genética , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Receptores de Antígenos de Linfócitos T/genética , Aberrações Cromossômicas , Células Clonais , Primers do DNA , União Europeia , Rearranjo Gênico do Linfócito T , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Padrões de Referência , Reprodutibilidade dos Testes
13.
Oncogene ; 34(19): 2426-36, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24954503

RESUMO

The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Anticorpos Monoclonais/uso terapêutico , Humanos , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
14.
Gene Expr ; 4(6): 345-56, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7549466

RESUMO

Members of the ras family of GTPases are involved in a wide variety of cellular processes including cell proliferation, differentiation, apoptosis, and transformation. The ras oncogene is one of the most frequently mutated genes in human cancer. In addition, other oncogene and tumor suppressor gene products are components of the signal transduction pathways in which Ras or other Ras-like GTPases play key regulatory functions. Current progress in the elucidation of these signal transduction pathways will be reviewed and the potential use of these insights for the development of novel therapeutic agents for the treatment of cancer will be discussed.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , GTP Fosfo-Hidrolases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/efeitos dos fármacos , Animais , Humanos
15.
Oncogene ; 33(5): 665-70, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23318432

RESUMO

A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Transformação Celular Neoplásica/genética , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Neoplasias Intestinais/metabolismo , Animais , Citometria de Fluxo , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/genética , Células Tumorais Cultivadas , Via de Sinalização Wnt/genética
16.
Leukemia ; 27(8): 1729-37, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23478664

RESUMO

In multiple myeloma (MM), angiogenesis is strongly correlated to disease progression and unfavorable outcome, and may be promoted by bone marrow hypoxia. Employing gene-expression profiling, we here identified the pro-angiogenic factor adrenomedullin (AM) as the most highly upregulated gene in MM cells exposed to hypoxia. Malignant plasma cells from the majority of MM patients, belonging to distinct genetic subgroups, aberrantly express AM. Already under normoxic conditions, a subset of MM highly expressed and secreted AM, which could not be further enhanced by hypoxia or cobalt chloride-induced stabilization of hypoxia-inducible factor (HIF)1α. In line with this, expression of AM did not correlate with expression of a panel of established hypoxia-/HIF1α-target genes in MM patients. We demonstrate that MM-driven promotion of endothelial cell proliferation and tube formation is augmented by inducible expression of AM and strongly repressed by inhibition of endogenous and hypoxia-induced AM activity. Together, our results demonstrate that MM cells, both in a hypoxia-dependent and -independent fashion, aberrantly express and secrete AM, which can mediate MM-induced angiogenesis. Thus, AM secretion can be a major driving force for the angiogenic switch observed during MM evolution, which renders AM a putative target for MM therapy.


Assuntos
Adrenomedulina/genética , Regulação Neoplásica da Expressão Gênica , Hipóxia/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mieloma Múltiplo/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transcrição Gênica
17.
Blood Cancer J ; 3: e139, 2013 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-24013661

RESUMO

Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 signalling as potential therapeutic targets for personalized treatment. Here, we report the prevalence of CD79B and MYD88 mutations and their relation to established clinical, phenotypic and molecular parameters in a large panel of DLBCLs. We show that these mutations often coexist and demonstrate that their presence is almost mutually exclusive with translocations of BCL2, BCL6 and cMYC, or Epstein-Bar virus infection. Intriguingly, MYD88 mutations were by far most prevalent in immune-privileged site-associated DLBCL (IP-DLBCL), presenting in central nervous system (75%) or testis (71%) and relatively uncommon in nodal (17%) and gastrointestinal tract lymphomas (11%). Our results suggest that MYD88 and CD79B mutations are important drivers of IP-DLBCLs and endow lymphoma-initiating cells with tissue-specific homing properties or a growth advantage in these barrier-protected tissues.

18.
Leukemia ; 26(10): 2159-71, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22918122

RESUMO

PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.


Assuntos
Imunoglobulinas/genética , Transtornos Linfoproliferativos/diagnóstico , Receptores de Antígenos de Linfócitos T/genética , DNA/análise , Rearranjo Gênico , Guias como Assunto , Humanos , Transtornos Linfoproliferativos/genética , Reação em Cadeia da Polimerase Multiplex
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