Analysis of the Effect of the Novel Histone Deacetylase Inhibitor, Depsipeptide (FK228/FR901228) on Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2499-2499
Author(s):  
Gladell P. Paner ◽  
Serhan Alkan
Keyword(s):  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Mantle Cell ◽  
Induced Apoptosis ◽  
Hodgkin's Lymphomas ◽  
H3 Acetylation

Abstract Background: Mantle cell lymphoma (MCL) comprises approximately 3–5% of the non-Hodgkin’s lymphomas and the vast majority of these patients are incurable. Histone deacetylases (HDAC) inhibitors are a new class of chemotherapeutic drugs that have been shown to inhibit cell proliferation and induce apoptosis in a variety of malignancies. Depsipeptide (FK228/FR901228) is a novel inhibitor of class I HDAC and was shown to be effective in patients with cutaneous T-cell lymphoma. Design: A MCL cell line, JeKo-1 was treated with varying concentrations of depsipeptide and analyzed for evidence of apoptosis. Apoptosis was analyzed by flow cytometry (Annexin and 7AAD staining) and by microscopic examination. The effect on the status of H3 histone acetylation and changes in the expression of the Bcl-2 family proteins (Bcl-2, Bcl-xl and Mcl-1) following treatment with depsipeptide were investigated by flow cytometric evaluation. Requirement for de novo protein synthesis and activation of JNK in depsipeptide-induced apoptosis was analyzed by treatment with cycloheximide (CHX) and JNK inhibitor (SP600125) prior to addition of depsipeptide respectively. The effect of depsipeptide in 5 primary MCL patient samples was then analyzed for morphologic evidence of apoptosis. Results: Depsipeptide (0.25 mM/L; 80%apoptosis) induced marked apoptosis in JeKo-1 cells and this was shown to be a dose dependent fashion following 12 hours incubation. There was increase in H3 acetylation, after treatment with depsipeptide. Bcl-2, Bcl-xl and Mcl-1 showed decreased expression in the depsipeptide treated samples. Treatment with CHX (100ng/ml and 500ng/ml) and SP600125 (20ml/L) had no effect to the ability of depsipeptide-induced apoptosis. Primary MCL cells of 5 patients also showed marked apoptosis with depsipeptide treatment. Conclusion: Depsipeptide causes increased H3 acetylation and induces apoptosis in MCL cell line and primary MCL cells. The mitochondrial apoptotic pathway is possibly altered by the depsipeptide treatment causing apoptosis, by down-regulation of Bcl-2, Bcl-xl and Mcl-1 proteins. Based on the recent phase I clinical trial demonstrating clinical response in cutaneous T cell lymphoma, our study supports the potential clinical utilization of depsipeptide in patients with MCL.

Cutaneous mantle cell lymphoma histomorphologically mimicking subcutaneous panniculitis‐like T‐cell lymphoma: Case report

2019 ◽  
Vol 46 (7) ◽  
pp. 538-541 ◽  
Author(s):  
Caroline Laggis ◽  
Rodney Miles ◽  
Deborah M. Stephens ◽  
Keith Duffy ◽  
Anneli Bowen ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Mantle Cell

Molecular and Biological Characteristics of Acquired Vorinostat-Resistant Cutaneous T-Cell Lymphoma Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1732-1732
Author(s):  
Chunlei Zhang ◽  
Xiang Zhang ◽  
Baoqiang Li ◽  
Madeleine Duvic
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Hdac Inhibitor ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Biological Characteristics ◽  
T Cell Lymphoma ◽  
Class I ◽  
Cutaneous T Cell Lymphoma ◽  
Inhibitor Resistance

Abstract Abstract 1732 Poster Board I-758 Vorinostat (suberoylanilide hydroxamic acid, SAHA), a pan-histone deacetylase (HDAC) inhibitor, has an overall response rate of 24-30% in two phase II studies of patients with cutaneous T cell lymphoma (CTCL). Since a considerable proportion of CTCL patients did not reach a partial response and loss of response could occur after only a few months, development of resistance became an important clinical problem. Although we have shown that constitutive activation of STAT signaling may be involved in resistance to vorinostat, the other mechanisms of resistance to vorinostat in CTCL are largely unknown. To further investigate mechanisms of vorinostat resistance, we have generated a vorinostat-resistant CTCL cell line (HH/VOR) from a parent vorinostat-sensitive HH CTCL cell line by long term exposure to stepwise increasing concentrations of vorinostat. The HH parental cells were cultured in increasing concentrations of vorinostat starting at 10 nM. Viable cells were then passaged into a higher concentration of vorinostat in 10 nM increments until a concentration of 1 μM vorinostat was reached. The HH/VOR cells were then maintained in complete RPMI1640 medium containing 1 μM vorinostat. We studied the molecular and biological characteristics of the vorinostat-resistant CTCL cells. Compared with the parental vorinostat-sensitive HH cells, the vorinostat-resistant HH/VOR cells were highly resistant to vorinostat-mediated growth inhibition and apoptosis. Of interest, the HH/VOR also exhibited cross resistance to another pan-HDAC inhibitor panobinostat and a class I HDAC inhibitor SNDX-275. The vorinostat-resistant HH/VOR cells had reduced accumulation of acetylated histones (H3 & H4) and decreased expression of class I and class II HDACs (1-11), and no expression of multi-drug resistant (MDR) efflux transporters. Moreover, the vorinostat-resistant HH/VOR cells had elevated DNA binding of NF-κB and increased expression of phospho-NF-κB p65 and phospho-STAT-1 compared with the parent sensitive HH cells. Co-treatment with the RXR-selective retinoid bexarotene selectively enhanced vorinostat-induced apoptosis in the vorinostat-sensitive HH and -resistant HH/VOR CTCL cell lines as well as in patients' Sézary cells compared to normal CD4+ T-cells. Taken together, our findings provide further evidence for the potential of vorinostat to cause acquisition of HDAC inhibitor resistance in CTCL. This acquired HDAC inhibitor resistance neither correlates with over-expression of HDACs nor with expression of MDR but correlates with abnormal activation of the NF-κB and STAT-1. Bexarotene may override this acquired resistance of CTCL cells to vorinostat and other HDAC inhibitors. Disclosures Zhang: Merck: Research Funding. Duvic:Merck: Honoraria, Research Funding, Speakers Bureau.

Functional characterization of an IL-7–dependent CD4+CD8αα+ Th3-type malignant cell line derived from a patient with a cutaneous T-cell lymphoma

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1056-1063 ◽  
Author(s):  
Eva Poszepczynska ◽  
Martine Bagot ◽  
Hamid Echchakir ◽  
Denis Martinvalet ◽  
Mohamed Ramez ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Proliferative Response ◽  
Cell Lymphoma ◽  
Functional Characterization ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
T Cell Clone ◽  
Tgf Β1

CDR3 of the functional rearranged T-cell receptor variable β region (TCR-Vβ) transcript was sequenced in order to demonstrate for the first time the identity between a long-term cultured T-cell line derived from a cutaneous T-cell lymphoma (CTCL) patient and the malignant T-cell clone present in the blood. The patient's peripheral blood lymphocyte-derived cultured T-cell line had a CD3+Vβ22+CD4+CD8+CD25−phenotype. It was named Pno and had been cultured for more than 1 year. Both fresh and long-term–cultured tumor cells proliferated highly in response to interleukin-7 (IL-7), and exogeneous IL-7 prevented Pno lymphocytes from apoptosis and maintained high levels of Bcl-2 expression. This unique malignant cloned lymphocyte line was further used to carry out functional studies. The results indicated that the CD3/TCR structures expressed by the Pno lymphocytes were functional because an immobilized anti-CD3 monoclonal antibody (mAb) or the combination of a soluble anti-CD3 mAb with submitogenic doses of phorbol 12 β-myristate 13 -acetate induced a proliferative response. Further, the CD2 and CD28 coreceptors were functional because they were able to induce a strong proliferative response upon their specific stimulation. Finally, the Pno T cell line had a Th3-type cytokine profile because it produced high amounts of the immunosuppressor cytokine tumor growth factor–β1 (TGF-β1). This high production of TGF-β1 may inhibit antitumor specific responses in CTCL.

scholarly journals Cyclin D1 expression in Peripheral T-Cell Lymphoma: A report of 2 cases

2021 ◽  
Vol 6 (4) ◽  
pp. 279-282
Author(s):  
Shweta P Rathi ◽  
Vinita Pant ◽  
Jay Mehta
Keyword(s):  
T Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Plasma Cell Myeloma ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Peripheral T Cell Lymphoma ◽  
Mantle Cell

: Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL), characterized by poor outcome, accounting approximately for 10%-15% of all non-Hodgkin lymphomas in the western countries, and with a higher prevalence in Asia. Cyclin D1 immunoreactivity is characteristically seen in mantle cell lymphoma. It is also observed in hairy cell leukemia, plasma cell myeloma and a proportion of diffuse large B-cell lymphomas, however its expression in peripheral T-cell lymphoma is rarely recorded. : We report two cases of peripheral T-cell lymphoma not otherwise specified with heterogeneous nuclear Cyclin D1 immunohistochemical overexpression, due to gene copy gain, a phenomenon similar to that observed in Mantle Cell Lymphoma.: Cyclin D1 expression can be seen in PTCLs, besides mantle cell lymphoma, hairy cell leukemia and plasma cell myeloma and underline the importance of molecular biology integration tests as a diagnostic tool to escape the pitfall.

Autologous Stem Cell Transplantation with Benda-BEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) in Aggressive Non Hodgkin and Hodgkin´s Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3982-3982 ◽  
Author(s):  
Thomas Noesslinger ◽  
Michaela Moestl ◽  
Christoph Tinchon ◽  
Elisabeth Koller ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Mantle Cell Lymphoma ◽  
Median Time ◽  
Autologous Stem Cell Transplantation ◽  
Cell Lymphoma ◽  
Conditioning Regimen ◽  
T Cell Lymphoma ◽  
Mantle Cell

Abstract Autologous Stem Cell Transplantation (ASCT) is standard of care in relapsed diffuse large B-cell lymphoma (DLBCL) and other lymphoproliferative disorders (relapsed Hodgkin´s disease, mantle or T-cell lymphoma). BCNU, Etoposide, Ara-C, Melphalan (BEAM) is a standard conditioning regimen, but BCNU is associated with interstitial pneumonia (range 2 to 20%) and a increased risk of death compared with busulfan or TBI based regimens. Therefore a less toxic regimen might improve the results in (relapsed) lymphoma patients. Bendamustine showed promising results in B- and T-cell lymphoma and dose escalation is safe and feasible. Here we report promising results with bendamustine replacing BCNU in the BEAM regimen described as Benda-BEAM, recently published in a phase two dose finding study (Visani, Blood 2011). Thirty-eight patients with Hodgkin´s (HL)(n=9) or Non-Hodgkin (n=29) lymphoma were consecutively treated with Benda-BEAM (bendamustine on two consecutive days at a dose of 200 mg/m2per day). Ten patients were diagnosed with DLBCL, also ten patients with mantle cell lymphoma, four patients with an anaplastic T-cell lymphoma, four patients with follicular lymphoma and one patient with an greyzone lymphoma. Twenty-four patients were male and fourteen female with a median age of 52 years (range 22-71) and 25% were above the age of sixty. The median lines of previous therapies were 2 (range: 1-4). 36 patients were treated with Benda-BEAM and 2 patients with mantle cell lymphoma received additionally Zevalin. All patients had chemosensitive disease and before transplantation 31 patients (82%) were in complete (CR) and 7 (18%) in partial remission (PR). A median number of 4,10*106 CD34+ cells/kg (range: 1,60-11,10) were infused. All patients showed engraftment with a median time to achieve an absolute neutrophil count > 1*109/L of 10 days (range 7-13) and to platelets >20*109/L of 11 days (range 5-26). The median time of fever was 6 days (range: 0 -22). The most common grade 3 and 4 toxicity during the whole treatment period were diarrhoea (n=10), mucositis (n=7) and febrile neutropenia (n=6), followed by nausea (n=4) and cardiologic toxicities (n=3). There were no pulmonary toxicities observed and no transplant related mortality occurred. After a median follow-up of 22 months, thirty-three patients were evaluable for response, with 21 patients (64%) still in CR, while 12 patients (36%) showed progression after a median time of 6 months after transplantation (range 2-22 months), Until today seven patients (21%) have died (5 DLBCL, 1 HL, 1 mantle cell lymphoma), all due to lymphoma progression. The 1-year PFS is 72% and the 1-year OVS 85%. Thus Benda-BEAM seems to be feasible with a promising response rate und a randomized phase II trial comparing Benda-BEAM with BEAM is planned. Disclosures Off Label Use: bendamustine as part of conditioning regimen before autologous stem cell transplanatation.

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