Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mantle cell lymphoma (MCL) is an aggressive subentity of non-Hodgkin lymphoma (NHL), responds poorly to therapy, is resistant to current therapeutic strategies and has the shortest survival of all lymphoma entities. The blastoid variant of mantle cell lymphoma (MCL-BV) has an even worse clinical outcome. The mechanisms of neoplastic transformation from normal mantle cells and the relationship to the rare blastoid variant are poorly understood. BCL2 is overexpressed in indolent B-cell NHL including MCL. In addition, other proteins of the BCL-family are overexpressed in MCL like BCLX, whereas the expression of BAX and BAK was not elevated in MCL. BCL2 independent apoptotic pathways are altered in MCL. CD40, which can mediate B-cell survival, is overexpressed in MCL. Furthermore, the expression of FAS which is known to be pro-apoptotic is markedly decreased favoring the CD40 mediated cell survival pathway in these cells. Besides overexpression of cyclin D1, the cyclin dependent kinases (CDK2 and CDK4) are highly expressed in MCL resulting in the phosphorylation of RB1, E2F release, and the cell cycle progression. The new technique of gene expression analysis by microarrays promotes more insight into the pathogenesis of MCL and discovery of altered cell signaling pathways, and the ability to predict subgroups of patients with different risk and probability of response to treatment.
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PMID:Altered apoptosis pathways in mantle cell lymphoma. 1506 Nov 96

CDK9 is a member of the CDC2-like family of kinases. Its cyclin partners are members of the CYCLIN T family (T1, T2a, and T2b) and CYCLIN K. The CDK9/CYCLIN T1 complex is very important in the differentiation programme of several cell types, controlling specific differentiation pathways. Limited data are available regarding the expression of CDK9/CYCLIN T1 in haematopoietic and lymphoid tissues. The aim of this study was to analyse the expression of the CDK9/CYCLIN T1 complex in lymphoid tissue, in order to assess its role in B- and T-cell differentiation and lymphomagenesis. CDK9/CYCLIN T1 expression was found by immunohistochemistry in precursor B and T cells. In peripheral lymphoid tissues, germinal centre cells and scattered B- and T-cell blasts in interfollicular areas expressed CDK9/CYCLIN T1, while mantle cells, plasma cells, and small resting T-lymphocytes displayed no expression of either molecule. CDK9/CYCLIN T1 expression therefore appears to be related to particular stages of lymphoid differentiation/activation. CDK9 and CYCLIN T1 were highly expressed in lymphomas derived from precursor B and T cells, from germinal centre cells, such as follicular lymphomas, and from activated T cells (ie anaplastic large cell lymphomas). Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma also showed strong nuclear staining. Diffuse large B-cell, Burkitt's lymphomas, and peripheral T-cell lymphomas, among T-cell lymphoproliferative disorders, showed a wide range of values. No expression of CDK9 or CYCLIN T1 was detected in mantle cell and marginal zone lymphomas. However, at the mRNA level, an imbalance in the CDK9/CYCLIN T1 ratio was found in follicular lymphoma and diffuse large B-cell lymphomas with germinal centre phenotype, and in the cell lines of classical Hodgkin's lymphomas, Burkitt's lymphomas, and anaplastic large cell lymphoma, in comparison with reactive lymph nodes. These results suggest that the CDK9/CYCLIN T1 complex may affect the activation and differentiation programme of lymphoid cells. The molecular mechanism through which the CDK9/CYCLIN T1 complex is altered in malignant transformation needs to be elucidated.
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PMID:CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation. 1525 98

Primary effusion lymphomas (PELs) represent a unique non-Hodgkin lymphoma that is consistently infected by Kaposi sarcoma herpesvirus (KSHV). PEL cells express high levels of the cell cycle inhibitor p27(KIP1) and yet proliferate actively. KSHV genome encodes a viral cyclin homolog, v-cyclin, which has previously been implicated in down-regulation of p27(KIP1) levels. To address how PEL cells can tolerate high p27(KIP1) levels, we investigated functional interactions between v-cyclin and p27(KIP1) using PEL-derived cell lines as a model system. Here we demonstrate that v-cyclin and p27(KIP1) stably associate in PEL cells in vivo suggesting an attractive model by which p27(KIP1) is inactivated in the actively proliferating PEL cells. Moreover, we show that v-cyclin and cyclin-dependent kinase 6 (CDK6) form an active kinase without p27(KIP1) and that CDK6 is the in vivo catalytic subunit of v-cyclin in PEL cells. These findings suggest that KSHV may promote oncogenesis in PEL by expressing v-cyclin, which both overrides negative cell cycle controls present in the PEL precursor cells and induces a strong proliferative signal via CDK6 kinase activity.
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PMID:KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas. 1527 92

The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G1-phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21CIP1 and p27KIP1. Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S- or G2-phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G1-phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.
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PMID:Aberrant expression of cell cycle regulators in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma. 1538 59

Classical Hodgkin lymphomas (cHL) have now been recognized as B-cell lymphomas with some exceptional cases of T-cell origin. In recent years, there has been accumulating evidence that Hodgkin and Reed-Sternberg (H/RS) cells, the presumed neoplastic-cell population in cHL, are characterized by a profound disturbance of the cell cycle and apoptosis regulation. The constitutive activation of the nuclear factor (NF)-kappaB pathway, which is considered to be involved in the proliferation and survival of H/RS cells. Moreover, substantial evidence that H/RS cells have defective cell cycle and apoptosis regulation has been provided by studies showing that these cells are characterized, in a large proportion of cases, by alterations of the p53, Rb and p27 tumor suppressor pathways, overexpression of cyclins involved in the G1/S and G2/M transition such as cyclins E, D2, D3, A and B1, overexpression of cyclin-dependent kinases such as CDK1, 2 and 6 and overexpression of anti-apoptotic proteins such as c-FLIP, bcl-xl, c-IAP2, X-linked I4P and survivin. Recent studies suggest that interleukin 13 (IL-13) is an important growth and survival factor in H/RS cells. Furthermore, the Epstein-Barr Virus (EBV), which is present in H/RS cells in about 30-50% of cHL, has been shown to affect the cell cycle and apoptosis regulation in cHL. The present review summarizes data with respect to the cell cycle and apoptosis deregulation in cHL.
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PMID:Cell cycle and apoptosis deregulation in classical Hodgkin lymphomas. 1579 9

Mantle cell lymphoma is a distinct entity among the non-Hodgkin's lymphomas characterized by a specific chromosomal translocation, the t(11;14)(q13;q32), overexpression of cyclin-D1 and frequent disease manifestations at extranodal sites. Mantle cell lymphoma remains difficult to treat and belongs to the lymphomas with the poorest long-term outcome. Recent advances in our understanding of lymphoma biology suggest that both alterations of the lymphoma cells themselves and interactions with the microenvironment are important for the growth and survival of the malignant B-cell clone. This novel approach to therapy is being exploited by evaluating drugs such as bortezomib and thalidomide that target interactions between tumor cells and cells of the microenvironment. Thus, with the use of novel therapeutic interventions, it is hoped that clinicians will be able to improve the outcome of patients with mantle cell lymphoma.
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PMID:Treatment of mantle cell lymphoma: targeting the microenvironment. 1600 55

Kaposi sarcoma herpesvirus (KSHV) infection is consistently associated with primary effusion lymphomas (PELs) that are non-Hodgkin lymphomas of B-cell origin. All PEL cells are latently infected with KSHV and express latent viral proteins such as the viral cyclin (v-cyclin), which has previously been implicated in down-regulation of cell-cycle inhibitor p27(KIP1) levels via phosphorylation on Thr187. PEL cells retain high levels of p27(KIP1) but yet proliferate actively, which has left the biologic significance of this p27(KIP1) destabilization somewhat elusive. We have recently demonstrated that v-cyclin and p27(KIP1) stably associate in PEL cells. Here we demonstrate that v-cyclin together with its kinase partner CDK6 phosphorylates the associated p27(KIP1) in PEL cells, which represent a biologically relevant model system for KSHV pathobiology. During latent viral replication p27(KIP1) was phosphorylated by v-cyclin-CDK6 predominantly on Ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of KSHV lytic cycle, v-cyclin-CDK6 phosphorylated p27(KIP1) on Thr187, which resulted in down-regulation of p27(KIP1) protein levels. These findings indicate that v-cyclin modulates the cell-cycle inhibitory function of p27(KIP1) by phosphorylation in PELs, and also suggest a novel role for v-cyclin in the lytic reactivation of KSHV.
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PMID:KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. 1616 6

Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E(2) (PGE(2)), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE(2) in T cells from healthy individuals. These data strongly suggest that PGE(2) is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma.
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PMID:Prostaglandin E2 impairs CD4+ T cell activation by inhibition of lck: implications in Hodgkin's lymphoma. 1642 48

Cyproheptadine, an inhibitor of the H1 histamine receptors, has recently shown activity in models of leukaemia and myeloma, presumably through inhibition of cyclin-D expression. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin-D1. We investigated the effect of cyproheptadine alone and in combination with the proteasome inhibitor bortezomib in models of MCL. The combination of these drugs was mathematically synergistic, producing significant reductions in the mitochondrial membrane potential leading to apoptosis. In a severe combined immunodeficient beige mouse model, cyproheptadine plus bortezomib demonstrated a statistically significant advantage compared to either agent alone.
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PMID:The anti-histaminic cyproheptadine synergizes the antineoplastic activity of bortezomib in mantle cell lymphoma through its effects as a histone deacetylase inhibitor. 1960 35

The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.
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PMID:Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. 1975 6


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