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1.
Blood Cancer J ; 4: e217, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24927406

RESUMO

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.


Assuntos
Doenças Ósseas/tratamento farmacológico , Dipeptídeos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Receptores Notch/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Distribuição Aleatória , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Leukemia ; 26(4): 806-13, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21946908

RESUMO

A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-κB (NF-κB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex context-dependent cross talk between Notch and NF-κB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the γ-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-κB signaling, interfering with processing of the NF-κB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-κB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-κB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-κB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.


Assuntos
Doença de Hodgkin/patologia , NF-kappa B/fisiologia , Receptores Notch/fisiologia , Células de Reed-Sternberg/fisiologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Doença de Hodgkin/tratamento farmacológico , Humanos , Antígeno Ki-1/fisiologia , Camundongos , Células NIH 3T3 , Receptores Notch/antagonistas & inibidores , Transdução de Sinais
4.
Curr Mol Med ; 11(3): 236-45, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21375490

RESUMO

Classical Hodgkin lymphoma (cHL) is now recognized as a B-cell-derived lymphoma which is characterized by only about 1% malignant pathognomonic Hodgkin and Reed-Sternberg (HRS) cells and an abundant infiltrate of reactive bystander cells. HRS cells are unique with respect to their lost B-cell-specific gene expression pattern and recurrent genetic lesions. Aberrant activity of Notch signaling, a highly conserved developmental pathway, acts as a negative regulator of the B cell program in HRS cells and thereby contributes to their reprogramming. Another striking feature and the major pathogenetic mechanism in HRS cells is constitutive NF-κB activation. A number of aberrations that contribute to canonical NF-κB activity in HRS cells have been described such as genetic lesions, deregulated receptor signaling and Epstein-Barr virus (EBV) infection. The importance of Notch and NF-κB signaling for cHL pathogenesis, their potential cross-talk and implications for future therapeutic applications are being discussed.


Assuntos
Doença de Hodgkin/metabolismo , NF-kappa B/metabolismo , Receptores Notch/metabolismo , Células de Reed-Sternberg/metabolismo , Transdução de Sinais , Animais , Antígenos CD , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma de Células B , Células de Reed-Sternberg/patologia
5.
Oncogene ; 30(15): 1831-40, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21119597

RESUMO

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies.


Assuntos
Proteínas de Ligação a DNA/genética , Linfoma/metabolismo , Proteínas Nucleares/genética , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Linhagem Celular , Humanos , Linfoma/patologia , Transativadores
7.
Leukemia ; 22(8): 1587-94, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18449208

RESUMO

Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed-Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed-Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma.


Assuntos
Linfócitos B/imunologia , Doença de Hodgkin/patologia , Receptor Notch1/metabolismo , Linfócitos B/citologia , Sequência de Bases , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Primers do DNA , Doença de Hodgkin/imunologia , Doença de Hodgkin/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Fator de Transcrição PAX5/metabolismo , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Phys Rev Lett ; 94(16): 162301, 2005 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15904216

RESUMO

We have measured rapidity densities dN/dy of pi+/- and K+/- over a broad rapidity range (-0.1 < y < 3.5) for central Au + Au collisions at square root(sNN) = 200 GeV. These data have significant implications for the chemistry and dynamics of the dense system that is initially created in the collisions. The full phase-space yields are 1660 +/- 15 +/- 133 (pi+), 1683 +/- 16 +/- 135 (pi-), 286 +/- 5 +/- 23 (K+), and 242 +/- 4 +/- 19 (K-). The systematics of the strange to nonstrange meson ratios are found to track the variation of the baryochemical potential with rapidity and energy. Landau-Carruthers hydrodynamics is found to describe the bulk transport of the pions in the longitudinal direction.

9.
Phys Rev Lett ; 94(3): 032301, 2005 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-15698255

RESUMO

Charged-particle pseudorapidity densities are presented for the d + Au reaction at sqrt[s(NN)] = 200 GeV with -4.2 < or = eta < or = 4.2. The results, from the BRAHMS experiment at BNL Relativistic Heavy-Ion Collider, are shown for minimum-bias events and 0%-30%, 30%-60%, and 60%-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semiclassical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt[s(NN)] = 19.4 GeV.

10.
Phys Rev Lett ; 93(10): 102301, 2004 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-15447397

RESUMO

Transverse momentum spectra and rapidity densities, dN/dy, of protons, antiprotons, and net protons (p-p) from central (0%-5%) Au+Au collisions at square root of S(NN)=200 GeV were measured with the BRAHMS experiment within the rapidity range 0

11.
Infection ; 32(3): 176-8, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15188079

RESUMO

We describe a 58-year-old patient with relapsing high-grade non-Hodgkin's lymphoma who exhibited exacerbation of posthypoxic action myoclonus during high-dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX) treatment for highly suspicious Pneumocystis jiroveci pneumonia (PCP). Three months previously the patient had experienced a hypoxic insult caused by respiratory arrest due to an anaphylactic reaction to antibiotic therapy. He had developed posthypoxic action myoclonus (Lance-Adams syndrome), which was well controlled by oral treatment with piracetam. However, after TMP-SMX therapy (115 mg/kg daily) was started for suspicion of newly developed PCP, posthypoxic action myoclonus worsened dramatically resulting in complete disability. Anti-myoclonic therapy with increased doses of piracetam and valproic acid did not significantly improve his clinical condition. Only when TMPSMX doses were reduced (38 mg/kg daily) on day 12 did action myoclonus cease within 2 to 3 days. We suggest that TMP-SMX can exacerbate posthypoxic action myoclonus.


Assuntos
Anti-Infecciosos/efeitos adversos , Mioclonia/induzido quimicamente , Pneumonia por Pneumocystis/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Humanos , Hipóxia/complicações , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Mioclonia/etiologia , Pneumocystis/efeitos dos fármacos
12.
Phys Rev Lett ; 93(24): 242303, 2004 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-15697798

RESUMO

We report on a study of the transverse momentum dependence of nuclear modification factors R(dAu) for charged hadrons produced in deuteron + gold collisions at sqrt[s(NN)]=200 GeV, as a function of collision centrality and of the pseudorapidity (eta=0, 1, 2.2, 3.2) of the produced hadrons. We find a significant and systematic decrease of R(dAu) with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at energies reached at BNL RHIC.

13.
Phys Rev Lett ; 91(7): 072305, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12935010

RESUMO

We present spectra of charged hadrons from Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV measured with the BRAHMS experiment at RHIC. The spectra for different collision centralities are compared to spectra from p+(-)p collisions at the same energy scaled by the number of binary collisions. The resulting ratios (nuclear modification factors) for central Au+Au collisions at eta=0 and eta=2.2 evidence a strong suppression in the high p(T) region (>2 GeV/c). In contrast, the d+Au nuclear modification factor (at eta=0) exhibits an enhancement of the high p(T) yields. These measurements indicate a high energy loss of the high p(T) particles in the medium created in the central Au+Au collisions. The lack of suppression in d+Au collisions makes it unlikely that initial state effects can explain the suppression in the central Au+Au collisions.

14.
Phys Rev Lett ; 90(10): 102301, 2003 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-12688991

RESUMO

We present ratios of the numbers of charged antihadrons to hadrons (pions, kaons, and protons) in Au+Au collisions at sqrt[s(NN)]=200 GeV as a function of rapidity in the range y=0-3. While the ratios at midrapidity are approaching unity, the K(-)/K(+) and p;/p ratios decrease significantly at forward rapidities. An interpretation of the results within the statistical model indicates a reduction of the baryon chemical potential from mu(B) approximately 130 MeV at y=3 to mu(B) approximately 25 MeV at y=0.

15.
Phys Rev Lett ; 88(20): 202301, 2002 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-12005556

RESUMO

We present charged-particle multiplicities as a function of pseudorapidity and collision centrality for the 197Au+197Au reaction at square root[s(NN)] = 200 GeV. For the 5% most central events we obtain dN(ch)/deta/(eta = 0) = 625+/-55 and N(ch)/(-4.7< or =eta < or =4.7) = 4630 +/- 370, i.e., 14% and 21% increases, respectively, relative to square root[s(NN)] = 130 GeV collisions. Charged-particle production per pair of participant nucleons is found to increase from peripheral to central collisions around midrapidity. These results constrain current models of particle production at the highest RHIC energy.

16.
Phys Rev Lett ; 87(11): 112305, 2001 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-11531519

RESUMO

Measurements, with the BRAHMS detector, of the antiproton-to-proton ratio at midrapidities and forward rapidities, are presented for Au+Au reactions at square root of [s(NN)] = 130 GeV, and for three different collision centralities. For collisions in the 0%-40% centrality range, we find N(&pmacr;)/N(p) = 0.64+/-0.04((stat))+/-0.06((syst)) at y approximately 0, 0.66+/-0.03+/-0.06 at y approximately 0.7, and 0.41+/-0.04+/-0.06 at y approximately 2. The ratios are found to be nearly independent of collision centrality and transverse momentum. The antiproton and proton rapidity densities vary differently with rapidity, and indicate a significant degree of collision transparency, although a net-baryon free midrapidity plateau (Bjorken limit) is not yet reached.

17.
Blood ; 94(9): 3129-34, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10556199

RESUMO

The transcription factor NF kappa B (NF-kappaB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-kappaB (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-kappaB/IkappaB system, which might be responsible for constitutive NF-kappaB activity, we have analyzed the inhibitor I kappa B alpha (IkappaBalpha) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin's disease patients, IkappaBalpha mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IkappaBalpha gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-kappaB-DNA binding activity. Furthermore, an analysis of the IkappaBalpha gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IkappaBalpha protein. We suggest that the observed IkappaBalpha mutations contribute to constitutive NF-kappaB activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin's disease (HD) patients. The demonstrated constitutive overexpression of IkappaBalpha in HRS cells evidences a deregulation of the NF-kappaB/IkappaB system also in the remaining cases, probably due to defects in other members of the IkappaB family.


Assuntos
Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , NF-kappa B/genética , Células de Reed-Sternberg/metabolismo , Sequência de Bases , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Dados de Sequência Molecular , Mutação , NF-kappa B/biossíntese , RNA Mensageiro/análise , RNA Mensageiro/genética , Alinhamento de Sequência
18.
Blood ; 94(6): 2065-71, 1999 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-10477736

RESUMO

Hodgkin's disease is histopathologically characterized by the relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and for yet unknown reasons by an abundant reactive background of T lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now report that eotaxin is strongly expressed in fibroblasts of Hodgkin's disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express this chemokine. In tissue culture, Hodgkin's disease tumor cells induce eotaxin expression in cocultured dermal fibroblasts in a concentration leading to a specific chemotactic response of a Th2 cell clone. Production of tumor necrosis factor-alpha (TNF-alpha) by Hodgkin/Reed-Sternberg cells appears to be responsible for this induction, because blocking of TNF-alpha by neutralizing antibodies prevented fibroblast eotaxin expression. Our data suggest that eotaxin is involved in the pathobiology of Hodgkin's disease by contributing to eosinophil and T-lymphocyte recruitment.


Assuntos
Quimiocinas CC , Quimiotaxia de Leucócito , Citocinas/genética , Doença de Hodgkin/patologia , Células de Reed-Sternberg/patologia , Pele/citologia , Transcrição Gênica , Células Cultivadas , Quimiocina CCL11 , Fatores Quimiotáticos de Eosinófilos/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/citologia , Fibroblastos/patologia , Fibroblastos/fisiologia , Regulação da Expressão Gênica , Células HeLa , Humanos , Hibridização In Situ , Linfonodos/patologia , RNA Mensageiro/genética , Células de Reed-Sternberg/fisiologia , Células Th2/fisiologia , Células Tumorais Cultivadas
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