bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of GSTpi Activity Increases the Sensitivity of MCL Cell Lines to Cisplatin, Cytarabin and Bortezomib, but Not Doxorubicin.
Authors: Paret Aurelie , Rolland Delphine , Ribrag Vincent , Coiffier Bertrand , Thieblemont Catherine 
Published: April 2020

Abstract
Preliminary data suggest drug resistance plays a major role in mantle cell lymphoma (MCL) and is linked to the aberrant expression of molecules such as Glutathion S-Transferase pi (GST pi) that catalyzes the nuclear conjugation of a broad variety of reactive electrophiles to the glutathion. We investigated in vitro the effect of the inhibition of GSTpi activity on the chemosensitivity of MCL cell lines by inhibiting the nuclear transport of GSTpi with Agaricus bisporus leptine (ABL).
Methods. Four MCL cell lines (Granta, NCEB, REC and UPN1) were analyzed for GSTP1 transcript expression by RT-PCR analysis and for GSTP1 genetic Ile105Val polymorphism. The effect of ABL on the 4 MCL cell lines viability was examined using cells pre-treated with ABL (40μg/ml) for 10 h followed by treatment with various concentrations of doxorubicin (DOX), cisplatin (CDDP), cytarabin and bortezomib for 48 h. The cell viability was estimated by MTT assay repeated three times.
Results. All the 4 cell lines expressed GSTPI transcript. Two of them (UPN1 and REC) were heterozygous for Ile105Val polymorphism, whereas NCEB and GRANTA were homozygous GSTP1-105Ile which has been correlated with an enzyme of high activity. DOX, CDDP, cytarabin and bortezomib have cytotoxic effects compared to non-treated cells, without any difference between the 4 MCL cell lines when considering their genetic polymorphism status. Co-administration of ABL caused a significant increasis of the cytotoxicity of CDDP and bortezomib in all cell lines (Student test: p between 0.0004 to 0.02 for CDDP; and p between 0.013 and 0.05 for velcade, depending on the cell lines). Co-administration of ABL caused an increasis of the cytotoxicity of cytarabin in 3 cell lines, the 4th being actually tested. No influence of ABL was detected on the cytotoxic effect of DOX. The analysis of the nuclear and the cytoplasmic localizations of GSTpi is currently realized by immunohistochemistry.
Conclusion. These results suggest that inhibition of the nuclear transfer of GSTpi increases in vitro the MCL sensitivity to CDDP, cytarabin and velcade but not DOX.
Heat Shock Protein 90 (HSP90) Inhibition by the Small Molecule 17-AAG Induces Cell Cycle Arrest and Apoptosis in Anaplastic Large Cell Lymphoma (ALCL) Irrespective of ALK Expression: Role of Akt, ERK and ALK Kinases in the Molecular Mechanisms of 17-AAG Anti-Tumor Activity.
Authors: Georgakis Georgios V. , Li Yang , Rassidakis George Z. , Samaniego Felipe , Medeiros L. Jeffrey , Younes Anas 
Published: April 2020

Abstract
Anaplastic Large Cell Lymphoma (ALCL) is a CD30 positive T-cell/null non-Hodgkin lymphoma which in many cases features a chromosomal translocation between tyrosine kinase nucleophosmin and anaplastic lymphoma kinase (NPM-ALK). Several groups demonstrated that patients with ALCL that do not express ALK have poor prognosis when treated with conventional chemotherapy, suggesting that these patients may require novel therapeutic approaches. Although the heat shock protein 90 (HSP90) has been shown to chaperone NPM-ALK, the effect of HSP90 inhibition on ALCL survival is not known. Furthermore, the effect of HSP90 inhibition on ALCL that do not express ALK is unknown. In the present study, the expression of HSP90 was evaluated in both ALK+ and ALK- primary and cultured ALCL cells. All of the ALK+ ALCL cases (21/21) and 58% (7/12) of the ALK- ALCL cases overexpressed HSP90, as determined by immunohistochemistry. In addition, 3 cell lines, two ALK+ (Karpas299 and SUDHL1) and one ALK- (Mac2A) were evaluated and were found to overexpress HSP90, as determined by western blot. The small molecule inhibitor 17-AAG induced antiproliferative effect in both ALK+ and ALK- ALCL derived cell lines. Inhibition of HSP90 in ALCL induces apoptosis, which was in part mediated by activation of the caspase pathway. Furthermore, 17-AAG depleted ALK kinase in ALK+ ALCL cells, in addition to depletion of the pro-survival Finally, AKT kinase. 17-AAG also decreased ERK phosphorylation, without altering total ERK levels in both ALK+ and ALK− ALCL cells. Moreover, 17-AAG reduced cyclin D1 and MDM2 levels which was associated with cell cycle arrest at G0/G1 phase. Finally, 17-AAG demonstared synergy with doxorubicin chemotherapy in the ALCL cell lines. Taken together, our data provide an excellent proof-of-principle for the potential therapeutic value of HSP90 inhibitors in ALCL, especially for ALK-negative subtype. Furthermore, our data suggest that 17-AAG may enahnce the effect of conventional chemotherapy in ALCL.
Evaluation of a New Prognostic Index for Peripheral T-Cell Lymphoma, Unspecified (PTCL-US).
Authors: McArthur Heather L. , Chhanabhai Mukesh , Randy Gascoyne D. , Joseph Connors M. , Kerry Savage J. 
Published: April 2020

Abstract
Background: Peripheral T-cell lymphoma, unspecified (PTCL-US) represents the largest subtype of PTCLs among Western populations. The prognosis of this heterogeneous group is poor with a 5-year overall survival (OS) of approximately 30%. The biological diversity of this subtype has prompted various attempts at refining clinical risk groups. For instance, the International Prognostic Index (IPI), first validated in DLBCL, has also been validated in PTCL-US in several studies. Recently, however, a new Prognostic Index for PTCL-US (PIT) has been proposed (Gallamini et al Blood103 (7): 2004). The purpose of this study was to apply the PIT to all patients with PTCL-US diagnosed and treated at the British Columbia Cancer Agency (BCCA) and to compare its prognostic utility with the IPI.
Methods: The BCCA Lymphoid Cancer Database was screened to identify all patients over 18 y diagnosed with PTCL-US by the World Health Organization classification system between January 1981 and June 2004. Patients were excluded if the diagnosis occurred outside of British Columbia or if the pertinent prognostic information was incomplete. Five year OS estimates were calculated for each variable in both the IPI (age &gt;60 y, LDH&gt; normal, PS ≥2, Stage III/IV and &gt;1 extranodal sites) and PIT models (age, LDH&gt; normal, PS ≥2 and bone marrow involvement). Five year OS estimates were then calculated for IPI groups 1, 2 and 3 (0/1, 2/3 and 4/5 factors, respectively) as well as PIT groups 1 through 4 (0, 1, 2 and 3/4 factors, respectively).
Results: Of the 134 patients identified, the median age was 61 y and the male to female ratio was 1.6. The predominant sites of extranodal involvement were bone marrow (10%), bone (6%), liver (4%), skin (4%), soft tissue (4%), lung (3%) and GI (3%). As demonstrated in figure 1, 5 year OS estimates were 73%, 24% and 22% for IPI groups 1, 2 and 3 (p=10−4), respectively and 76%, 35%, 25% and 19% for PIT groups 1 through 4, respectively (p=10−4 ). There was no difference between the prognostic models in the subset of 107 (80%) patients treated with CHOP-based chemotherapy.
Conclusions: Although the PIT was as effective as the IPI in defining clinical risk groups among PTCL-US patients, it did not provide any additional information in this study. Since the IPI is a well-established, familiar tool with similar prognostic capacity, it is reasonable to continue to apply this model in PTCL-US. With ongoing advances in gene expression profiling, it is likely that new biological models will emerge which may be used in combination with the IPI to better prognosticate this heterogeneous group.
Figure Figure
Proteomic Analysis of Shed Membrane Microparticles from Malignant Lymphoid Cells: A New Tool for Membrane Proteins Studies.
Authors: Mauvieux Laurent , Miguet Laurent , Felden Claire , Freyssinet Jean-Marie , Herbrecht Raoul , Potier Noelle , van Dorsselaer Alain 
Published: April 2020

Abstract
Plasma membrane antigens are critical for the classification and diagnosis of chronic mature B-cell lymphocytic malignancies, illustrated by the extensive use of the Matutes score for CLL diagnosis. Nevertheless, new surface markers that could be detected using flow cytometry are still needed for the diagnostic and classification of a number of chronic lymphoid malignancies. In this aim, proteomic tools could be of great interest in order to detect such antigens, but analysis of plasma membrane proteins is limited by the difficulty of their purification and separation of membrane proteins with usual 2-dimensional electrophoresis have often been poor. For all these reasons, we proposed to take advantage of the physiological production of plasma membrane microvesicles in order to study plasma membrane proteins of malignant lymphoid cells. Indeed, when eukaryotic cells are submitted to stress conditions (including mitogenic activation or apoptosis), the constitutive asymmetry between the inner and outer leaflet of the plasma membrane is disrupted and fragments are released from the plasma membrane, constituting the so-called microparticles (MPs). Although MPs reflect at least in vitro the cell state, little is known on their protein composition. We describe here the first set of experiments aiming to characterize the MPs proteome. First, two ways of triggering MPs formation from a T-lymphocytic cell line were analyzed using a 1D-gel approach coupled with Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). 390 proteins were identified in MPs among which 34% were localized to the plasma membrane. Replicate experiments from independent samples identified only very few nucleus or organelles proteins, but revealed a broad representation of plasma membrane proteins including seventeen hematopoietic clusters of differentiation and numerous signal transduction proteins. This approach was then successfully applied to circulating cells of a small-lymphocytic B-cell lymphoma. 414 proteins were identified in MPs, including 118 membrane proteins. In addition to various CD antigens, annexins, immunoglobulin chains and HLA antigens, proteins involved in the B-cell receptor signal transduction were recovered, including tyrosine kinases LYN, SYK, BTK, CSK, but also phospho-inositide 3-kinase (PI3K) phospholipase Cγ (PLCγ 2), hemopoietic cell kinase (HCK) and JAK1.
Proteomic analysis of MPs may represent a new tool to study plasma membrane proteins, displaying the advantages of reproducibility, minimal organelle contamination and potentially applicable to most cell types. Extensive proteomic analysis of MPs may thus be a way to investigate differential expression of plasma membrane components and to identify new pathology markers that could help for diagnosis and classification.
Minimal Residual Disease (MRD) in Adult T-Cell Leukemia/Lymphoma (ATLL) Evaluated by HTLV-1 Proviral Load and Soluble IL-2 Receptor Level in Peripheral Blood.
Authors: Tsukasaki Kunihiro , Takemoto Shigeki , Taguchi Hirokuni , Masuda Masato , Ikeda Syuichi , Yoshida Shinichiro , Suzushima Hitoshi , Uike Naokuni , Saburi Yoshio , Kawano Fumio , Yamamura Masaomi , Sueoka Eizaburo , Miyahara Masaharu , Tomonaga Masao 
Published: April 2020

Abstract
Background: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type-1 (HTLV-1). Age, advanced PS, high LDH value, hypercalcemia and multiple visceral involvements were reported as prognostic factors for ATLL. Although initial therapy is often successful for aggressive ATLL with response rate of 50–80%, relapse (Rel) or progressive disease (PD) is frequent with 2 year-survival of 15–45% after chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). That means clinical evaluation of response is not sufficient to predict the prognosis of ATLL. HTLV-1 proviral load (PL) and soluble IL-2 receptor (sIL-2R) level have been reported to be associated with disease activity in ATLL.
Method: We prospectively analyzed MRD in aggressive ATLL, acute(A)-, lymphoma(L)- or unfavorable chronic(C)-type, by measuring PL and sIL-2R level in peripheral blood, using real time PCR for Tax region of the virus and conventional ELISA, respectively.
Results: PL and sIL2-R were measured just before start of therapy and every 2 months for 1 year unless Rel/PD happens in 78 pts. Median survival time was 7.3 months. Before chemotherapy (n=62), PL was high in order of C, A, and L, and sIL-2 level was of A, L and C, respectively. Neither PL nor sIL2-R level at first point was prognostic factor for pts having chemotherapy, while sIL2-R level, but not PL, was a prognostic factor in trend for pts having allo-HSCT (n=16). Median of the follow up for MRD was 4 months in the former and 6 months in the latter, respectively. In general, sequential data of both reflected disease activity in each case. PL and sIL-2R level were lower during complete response (CR) than partial response (PR), and elevated at Rel/PD. In cases with CR after chemotherapy, PL decreased gradually in 2 to 4 months and was still detected at levels of 1 to 10% during CR. In CR cases after HSCT, PL was often not detected (&lt;0.2%) in 2 months, while sIL-2R level was still high probably reflecting GVHD activity. In CR cases with chemotherapy as compared to PR cases, increase in PL and/or sIL-2R level frequently preceded clinical relapse.
Conclusions: These results in aggressive ATLL suggest that; 1) sIL2-R level, but not PL, was a potential prognostic factor for pts having HSCT. 2) PL was better than sIL-2R in estimation of MRD after HSCT. 3) Exacerbation of PL and/or sIL2-R was more useful for prediction of relapse in CR cases as compared to PR cases after chemotherapy.
Relative Risk of Cardiovascular Disease after Treatment for Aggressive Non-Hodgkin’s Lymphoma.
Authors: Moser E. C. , Noordijk E. M. , van Leeuwen F. E. , le Cessie S. , Baars J. W. , Thomas J. , Carde P. , van Glabbeke M. , Meerwaldt J. H. , Kluin-Nelemans J. C. 
Published: April 2020

Abstract
Cardiovascular complications after therapy for Hodgkin lymphoma have been related to radiotherapy on the mediastinum, but have only incidentally been studied in NHL. As cardiovascular disease occurs commonly in the normal population, it is important to realize that risk factors as age, hypertension and life-style (diet and smoking) may be more outspoken in patients with NHL, who are generally older than patients with Hodgkin lymphoma. Moreover, although most patients with aggressive NHL will initially receive only chemotherapy, many will be treated with more than one therapy modality, incorporating stem cell transplantation or radiotherapy, because of early failure or relapses. Therefore, risk estimation of cardiovascular disease in NHL patients requires comparison to population-based rates. Here, we evaluated whether patients with aggressive NHL treated in 4 EORTC trials between 1980–1999 have an increased excess cardiovascular risk, compared to Dutch population rates. Relative risks (RR) and absolute excessive risks (AER per 1000 person-years) of cardiovascular disease were determined in 476 (Dutch and Belgian) patients and compared to incidence rates from the Continuous Morbidity Registry Nijmegen. Analyses were restricted to those patients treated with at least 6 cycles of doxorubicin-based chemotherapy and with a minimal follow-up time of 0.5 years. Only serious late events requiring daily medication and/or clinical interventions were recorded. Cumulative incidences of cardiovascular disease were estimated in the competing risk model by Gray with death by any cause as competing event. The overall cumulative incidence of cardiovascular disease was 12% at 5 and 22% at 10 years. At a median follow-up of 8.4 years, 66 cases of chronic heart failure (RR 5.4, 95% CI 4.1–6.9, AER 20.8), 17 myocardial infarctions (RR 1.2; 0.8–1.8, AER 0.8), 12 strokes (RR 1.8; 1.1–2.4, AER 1.5) and 9 other large vessel occlusions were registered. The large vascular events including strokes occurred in 16/21 patients after radiotherapy given in the same area. Pre-existent hypertension, NHL at young age (&lt;55 years) and (any) salvage treatment increased risk of cardiovascular disease. Excess risk for myocardial infarction or stroke after radiotherapy on respectively the mediastinum or neck depended on cumulative radiation dose and was only seen after more than 40 Gy. Excess risk for chronic heart failure was registerd in both non-irradiated (RR 4.4) and irradiated patients, with an extremely high RR of 32 (13.7–57.0) if &gt;40 Gy had been given. In conclusion, NHL patients treated with doxorubicin-based chemotherapy, especially those who are young, have hypertension, or received salvage treatment or radiotherapy above 40 Gy, are at high risk of cardiovascular disease and need lifelong monitoring in this regard.
High Frequency of AML1 Mutations in Patients with Chronic Myelomonocytic Leukemia.
Authors: Shih Lee-Yung , Huang Chein-Fuang , Liang Der-Cherng , Shih Yu-Shu , Wu Jin-Hou , Dunn Po , Wang Po-Nan , Kuo Ming-Chung 
Published: April 2020

Abstract
Transcription factor AML1 is essential for normal hematopoiesis. AML1 mutations have been described in myelodysplastic syndrome (MDS), especially in therapy-related MDS but were rarely examined in patients with chronic myelomonocytic leukemia (CMML). We sought to determine the frequency of AML1 mutations in CMML and to assess their role in the progression of CMML to AML. Mutation analysis of AML1 was performed on bone marrow samples from 63 patients with CMML by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the coding sequences of AML1 gene from exon 3 through exon 8. AML1 mutations were detected in 24 of 63 patients (38%) at initial diagnosis, 16 patients had mutations located in Runt homology domain (RHD) (exons 3–5), and 8 had mutations located in the C-terminal region (exons 6–8). One patient had 2 missense mutations in RHD and another one had 2 frameshift mutations in RHD. Taken together, the patterns of 26 mutations consisted of 7 missense mutations, 5 nonsense mutations, 2 silent mutations and 12 frameshift mutations. Ten of 24 patients (41.7%) with mutations progressed to AML compared to 13 of 39 patients (33.3%) without mutations, no difference was observed in the risk of AML transformation between the two groups (P=0.593). Of the 23 patients who progressed to AML, 17 also had bone marrow samples available at AML transformation for mutation analysis. AML1 mutations were detected in 8 of 17 patients at both diagnosis of CMML and AML transformation, all exhibited identical patterns at both phases, with no loss or gain of mutations during AML progression. There were no differences in age, sex, blood counts, percentage of blasts in bone marrow or peripheral blood, subtype of CMML (1 or 2), and cytogenetic risk group between patients with AML1 mutations and those without mutations. Time to AML transformation and overall survival of patients with AML1 mutations did not differ from those without AML1 mutations. Our study showed that AML1 mutations were frequently detected in CMML, with 70% located in RHD. All mutant clones remained identical at initial diagnosis and AML transformation, suggesting that AML1 mutations play an important role in the leukemogenesis in this subset of patients with CMML.
Identification and Functional Significance of Genes Regulated by Structurally Different ABL Kinase Inhibitors.
Authors: Nunoda Kousuke , Tauchi Tetsuzo , Takaku Tomoiku , Sumi Masahiko , Okabe Seiichi , Sashida Goro , Akahane Daigo , Ohyashiki Junko H. , Ohyashiki Kazuma 
Published: April 2020

Abstract
Imatinib is an ABL-specific inhibitor that binds with high affinity to the inactive conformation of the BCR-ABL tyrosine kinase and has been shown to be effective in the treatment of chronic myelogenous leukemia. Dasatinib is an ATP-competitive, dual-spesific SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical stand point, dasatinib is particular attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant CML patients. In the view of the fact that the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on a wild type p210 BCR-ABL expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 hrs, and gene expression data was obtained from three independent microarray hybridizations. Almost all of the imatinib- and dasatinib- responsive genes appeared to be similarly increased or decreased in K562 cells; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. The genes whose expression was affected by imatinib and dasatinib were categorized into different functional groups based on their biological function, and genes in the cell proliferation and apoptosis categories were examined in detail. Imatinib and dasatinib affected the expression of several cyclin-dependent kinases (CDK2, CDK4, CDK6, CDK8, and CDK9), cell division cycle genes (CDC6, CDC7, CDC25C, and CDC34), and cyclones (cyclin A2, C, D2, D3, E1, E2, F, G1, G2, and H). Imatinib and dasatinib also modulated the expression of apoptosis-related genes including APAF1, BAK1, BCL2, BCL10, MCL1, CASP3, and CASP6). One of the distinct genes which are selectively modulated by dasatinib are CDK2 and CDK8, which had a maximal fold reduction of &lt;8-fold in microarray screen. Immunoblotting confirmed that gene expression changes induced only by dasatinib correlated with changes in protein expression. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. The siRNA to CDK2 or CDK8 specifically reduced cdk2 or cdk8 in K562 cells. K562 cells pretreated with CDK2 or CDK8 siRNA showed the additive growth inhibition with imatinib but not with dasatinib. These finding demonstrate that the additive/synergistic growth inhibition by imatinib and dasatinib may be mediated by CDK2 and CDK8.