bluuebunny/crossref_metadata_2025_split huggingface dataset:
Charcterization of a Newly Established Megakaryo/Erythroid Leukemia Cell Line, JAS-R.
Authors: Yamada Hisashi , Horiguchi-Yamada Junko , Sekikawa Tetsuaki 
Published: April 2020

Abstract
A few leukemic cell lines which express megakaryo/erythroid markers are available. We recently established a new cell line, designated JAS-R, from a 64-year-old patient with acute megakaryocytic leukemia (AML M7). Immunophenotyping showed that JAS-R cells were positive for CD4, CD7, CD13, CD33, CD41, CD61 and glycophorin A. Chromosome analysis was composite karyotype, but no major translocation abnormalities were observed. Electron-microscope examination disclosed that JAS-R had bleb like surface margin and a-granules in cytoplasm. Major four proteins which exist in a-granule were expressed high levels in JAS-R by RT-PCR. To further characterize JAS-R from four other megakaryo/erythroid cell lines (MEG-01, CMK, K562 and KU812), the comparison of gene expression profiling was studied by using oligo-DNA array. JAS-R was categorized as most different cell line among them. Of note, JAS-R secreted erythropoietin and expressed erythropoietin-receptor. But erythropoietin-neutralizing antibody failed to inhibit the growth of JAS-R cells. JAS-R may be useful for the further understanding of megakaryo and erythroid regulation and for the study of megakaryo/erythroid leukemogenesis.
Analysis of Both Clonal Functional and Non-Functional Immunoglobulin Heavy Chain (IgH) Rearrangements in Waldenström’s Macroglobulinemia.
Authors: Martin-Jimenez Patricia , Balanzategui Ana , Ocio Miguel E. , Alcoceba Miguel , Sarasquete Maria E. , Aguilera Carmen , Portero Jose A. , Calvo Javier Fernandez , Frade Javier Garcia , Chillon Maria C. , Diaz Guadalupe , Armellini Adriana , Garcia-Sanz Ramon , Gonzalez Marcos , Miguel J.F. San 
Published: April 2020

Abstract
Introduction: Waldenström’s Macroglobulinemia (WM) is an uncommon lymphoproliferative disorder characterized by bone marrow infiltration of the lymphoplasmocytic cells and IgM monoclonal gammopathy. The normal counterpart of the WM malignant cell is believed to be a post germinal-center B cell. However, the low frequency of WM has hampered investigation into Immunoglobulin Heavy Chain (IgH) rearrangements in large series of patients and whether preferential use of specific genetic segments or non-functional rearrangements exits.
Aim: Molecular characterization in a large cohort of WM patients analyzing their functional, complete VDJH, and non-functional, incomplete DJH, IgH rearrangements, the pattern of somatic hypermutation (SHM) and gene segment usage.
Patients and methods: 47 patients with unequivocal diagnosis of WM were included in the study. Bone Marrow samples (always with more than 10% of tumor cell) were used for amplification of clonal rearrangements employing the Biomed-2 strategy (Leukemia2003; 17; 2257), followed by direct automated sequencing in ABI 377 DNA sequencer using Big-Dye terminators (Applied Biosystems, Foster City, CA).
Results: All patients showed a monoclonal amplification of at least one VDJH or DJH rearrangement. VDJH monoclonal rearrangements were detected in 42/47 (89.3%) patients while DJH were observed in 20 (42.5%) patients.
VH, DH and JH gene segment usage: VH3 gene segment was the most commonly represented family (76,2%) while the other gene segments were scarcely detectable, and VH5 was totally absent. In the complete VDJH rearrangements, DH6 was the family most commonly represented while DH2 (45%) and DH4 (30%) were the most common in the incomplete DJH rearrangement. Regarding JH elements, JH4 (38%) was the most represented in the complete rearrangements and JH5 (46%) in the incomplete rearrangements.
Somatic hypermutation: SHM were observed in all except two of the cases (94%, 34 of 36 cases), in which the study could be performed. (median 9,38; range2.9–16.6). In the remaining clonal cases (6 cases, 14.3%) no amplification of FR1 region was obtained, also suggesting the presence of SHM.
Conclusions: In this series of patients, we observed the presence of incomplete rearrangements with an incidence similar (44%) to that described in multiple myeloma. The preferential usage for determined families of genetic segments, in VDJH and in DJH, suggests the presence of positive and negative selection processes. Finally, the majority, (94 %) of the cases, presented SHM, although the presence of two patients lacking in SHM suggests a pre-follicular origin for some WM cases.
NOTCH1 Is Targeted by Ig Translocations in NHL.
Authors: Wlodarska Iwona , De Wolf-Peeters Chris , Cools Jan , Minnei Francesca , Bosly Andre , Delos Monique , Michaux Lucienne , Vandenberghe Peter , Hagemeijer Anne , Marynen Peter 
Published: April 2020

Abstract
NOTCH1 signaling is required for normal T cell development. Its aberrant activation by either the rare t(7;9) translocation or frequent mutation(s) in T-ALL points to an important role of this gene in T cell lymphomagenesis. So far, a pathogenetic role for NOTCH1 in B-cell malignancies is unknown. We report here evidence for NOTCH1 rearrangements in B-cell lymphoma. Two novel 9q34 translocations involving either the 14q32/IGH or the 22q11/IGL locus were identified in 2 patients with respectively, Richter syndrome (RS) and follicular lymphoma (FL). The first case showed a clone with a sole trisomy 12 detected by FISH in 25% of interphase cells and a subclone with an additional dic(9;14)(q34;q32) in 60% of cells from a lymph node sample. The karyotype of the FL case was characterized by the typical t(14;18)(q32;q21)/IGH-BCL2 accompanied by additional t(8;14)(q24;q32)/IGH-CMYC and t(9;22)(q34;q11). FISH analysis of dic(9;14) and t(9;22) using a set of BAC clones mapped both 9q34 breakpoints to the 5′end of NOTCH1. These breakpoints were different from the breakpoint of t(7;9)(q35;q34) (intron 24), as demonstrated by FISH analysis of the T-ALL SUPT1 cell line. NOTCH1 rearrangements showed to be rare in B-NHL. Any of the additional 30 lymphoma cases with structural aberrations of 9q34 analyzed by FISH showed rearrangement of this gene. So far, aberrant activation of NOTCH1 in the reported cases with dic(9;14) and t(9;22) could not be documented: both lymphomas but also 9 control CLL and FL cases without 9q34 aberrations revealed expression of NOTCH1 mRNA by RT-PCR, its ligand JAGGED2 and its transcriptional target HES1. This expression pattern indicates a ligand-driven NOTCH1 signaling in all analyzed cases, possibly reflecting its physiological activation in progenitor B cells and thus, masking the presumed aberrant activation of NOTCH1 in present lymphomas. Whether IGH/L-NOTCH1 translocations in B-NHL lead to the generation of truncated/activated NOTCH1 proteins, similar to these found in T-ALL, remains to be determined. Particularly interesting is the association of the dic(9;14) with Richter transformation in the first case suggesting that rearrangement of NOTCH1 could be responsible for a rapid progression of the underlied CLL. In the second case of FL, t(9;22) seemed to be associated with the evolution of t(14;18)-positive karyotype. These findings contrast with t(7;9), considered as a primary oncogenic event in development of T-ALL. Further molecular and immunohistochemical investigations of the reported cases are in progress.
Transcriptome Analysis of Pediatric cALL Versus Normal Fetal B Cells Reveals a Novel Signature of the Malignant Phenotype.
Authors: Richter Guenther , Hattenhorst Uwe E. , Roessler Sabine , Staege Martin S. , Hansen Gesine , Burdach Stefan 
Published: April 2020

Abstract
Differential gene expression profiling of pediatric common acute lymphoblastic leukemia (cALL) versus non-malignant tissues enables identification of aberrantly expressed genes in malignant cells, facilitating discrimination of leukemic from normal cells and possibly revealing specific disease mechanisms. Expression patterns of 29 pediatric cALL samples were analyzed by use of high-density DNA microarrays HG-U133A. Leukemic patients’ bone marrow samples were compared to sorted B cells from cord blood of healthy donors expressing CD19 and CD10 surface antigens. Principal component analysis clearly distinguished leukemia samples from normal controls. Significance analysis of microarrays revealed 723 genes significantly up-regulated, and 617 down-regulated genes in leukemic cells. Independent validation of deregulated genes by RT-PCR was chosen to address enrichment limitations of controls. A comparison to previous publications investigating genetically defined subsets of cALL revealed only 5 – 22% match with our differentially expressed genes. Furthermore, class prediction with only 14 differentially expressed genes correctly classified tumors and controls not included in the training set and hitherto not investigated samples including 3 leukemic tumor lines (NALM-6, CALL-2, 697) as cALL. Interestingly, terminal deoxynucleotidyl-transferase (DNTT) as well as in the context of cALL unknown genes, were found to be the strongest predictive genes for the malignant phenotype signifying the diagnostic value of our approach.
Transcriptional Profiling of Epstein-Barr Virus (EBV) Genes and Host Cellular Genes in Nasal NK/T-Cell Lymphoma and Chronic Active EBV Infection.
Authors: Zhang Yu , Ohyashiki Junko H. , Takaku Tomoiku , Shimizu Norio , Ohyashiki Kazuma 
Published: April 2020

Abstract
Nasal NK/T-cell lymphoma is a uniquely aggressive and incurable subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein-Barr virus (EBV). Since necrosis is the common feature of nasal NK/T-cell lymphoma, the biological features of lymphoma cell are poorly understood because of the difficulty in obtaining sufficient viable specimens. The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. Although the molecular biology of EBV and B cell transformation has been extensively studied for years, little is known about the host-virus interaction in EBV-related NK- and T-cell malignancies. This study aimed to investigate the virus-host interaction in two types of EBV-associated NK/T-cell LPD which may clarify the possible association between infection and cancer. We attempted transcriptional profiling of EBV genes using a novel viral DNA microarray, HHV-4 Viruchip®, in addition to host cellular gene expression profiling using human oligonucleotide DNA microarrays, seeking to evaluate the possible role of EBV-host interaction in nasal NK/T-cell lymphoma and CAEBV infection. We used six cell lines with EBV-associated T/NK-cell LPD: SNK-1, SNK-6 and SNT-8 were isolated from nasal NK/T-cell lymphoma, and SNK-10, SNT-13 and SNT-16 were isolated from the peripheral blood of patients with CAEBV infection (Zhang Yu, et al., Br. J. Haematol., 121: 805–814, 2003). We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was preferentially high in cell lines from CAEBV infection. We also analyzed the gene expression patterns of host cellular genes using a pathway-focused human oligonucleotide DNA microarray (NCBI GEO accession number: GPL1919 and GPL 1920). We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD, and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.
Efficacy and Safety of a Single-Course of Yttrium-90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in Patients with Relapsed or Refractory Mantle Cell Lymphoma (MCL) After/Not Appropriate for Autologous Stem Cell Transplantation (ASCT) - A Phase II Trial of the European MCL Network.
Authors: Weigert Oliver , von Schilling Christoph , Rummel Mathias J. , Pezzutto Antonio , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin 
Published: April 2020

Abstract
Radioimmunotherapy (RIT) has demonstrated high clinical efficacy in the treatment of B-cell non-Hodgkin’s lymphoma (B-NHL) and has been approved for relapsed indolent and transformed B-NHL. However little is known about RIT with Zevalin® in patients with mantle cell lymphoma (MCL), a lymphoma subtype characterized by indolent morphology but aggressive clinical course with a median survival of only 3– 4 years and virtually no long-time survivors. Patients with relapsed or refractory CD20 positive MCL after/not appropriate for ASCT, WHO performance status &lt;2, age &lt; 75 years and adequate function of the bone marrow (ANC &gt;1,500/mm3, platelets &gt;100,000/mm3), liver and kidneys were eligible for this trial. Patients were excluded if they had &gt; 25% bone marrow involvement, prior allogeneic stem cell transplantation or RIT, known CNS lymphoma, HIV infection or other concurrent severe medical disease. Patients with normal platelet counts received a dose of Zevalin® at 14.8 MBq 90Y/kg (to a maximum dose of 1,184 MBq), whereas those with platelet counts &lt;150,000/mm3 received 11.1 MBq 90Y/kg. Currently, 14 patients have been enrolled and 6 are eligible for evaluation of treatment response. The median age was 68 years (range 56 – 71), 9 patients were male. All patients had been previously treated with Rituximab containing regimens. The median number of prior regimens was 4 (range 2–6). Zevalin® treatment was generally well tolerated, with the most common toxicities being hematologic. Thrombocytopenia grade 3 and 4 was observed in 2 and 4 patients, respectively, without significant bleeding complications. Granulocytopenia grade 3 and 4 occurred in 3 and 2 patients, respectively and 1 patient developed a grade 4 infectious complication. This patient also developed non-hematologic toxicities grade 3 and 4 consisting of sepsis-associated hepatotoxicity, diarrhoea and pleural empyema. Partial responses were observed in 2 of 6 patients (33.3 %), another patient experienced a stable disease. Median progression free survival (PFS) was 3.9 months in this high risk group. Preliminary analysis suggests that patients with bulky disease did not respond to radioimmunotherapy. The clinical course of the total group of this ongoing trial will be presented at the meeting. The observed responses to Zevalin® in heavily pretreated patients with MCL are promising, however median PFS was short-lived. Thus, a prior debulking strategy with combined immuno-chemotherapy is recommended to potentially achieve a longer duration of remission. Accordingly, in future trials RIT should be applied earlier in the treatment algorithm of MCL.
A Pilot Study of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in Patients with Relapsed and Refractory Classical Hodgkin Lymphoma (HL): Delivering Cross Fire Radiation by Targeting Reactive B Cells in the Microenvironment.
Authors: Younes Anas , Romaguera Jorge E. , McLaughlin Peter , Wong Franklin 
Published: April 2020

Abstract
Both non-Hodgkin lymphoma (NHL) and HL are radiosensitive tumors. Although the efficacy of radioimmunotherapy (RIT) targeting CD20 antigen has been established in several types of B-cell NHL, no data exisit on the potential use of this approach in classical HL. The malignant Hodgkin and Reed-Sternberg (HRS) cells of HL infrequently express CD20 suggesting that classical HL may not be the optimal tumor to be targeted by this approach. However, HRS cells are frequently surrounded by reactive B lymphocytes that express CD20. Therefore, we hypothesized that targeting reactive B cells in HL microenvironment by RIT could deliver effective radiation dose to HL lymph nodes killing HRS cells by cross-fire effect. To test this hypothesis, we treated 4 patients with relapsed classical HL with Zevalin RIT. During the imaging phase, patients received a slow intravenous infusion of rituximab (250 mg/m2) followed by an intravenous injection of 4–5 mCi of In-111 labeled anti-CD 20 (In-111 Zevalin). Whole-body scans were performed at 2–4 hours and 40–48 hours after injection using a Siemens dual-head gamma camera. Simultaneous anterior and posterior projections were obtained at these time points. After ruling out any unfavorable biodistribution of Zevalin was confirmed on images at both time points, patients underwent the treatment phase which consisted of rituximab (250 mg/m2) followed by Y-90 anti-CD 20 (Y-90 Zevalin). To-date 4 patients are enrolled on study (ages 25, 31, 65, and 74 years). Two patients received prior ASCT, and 2 were treated after failing ABVD chemotherapy alone. All patients received 0.4 mCi/Kg up to a maximum dose of 32 mCi. Normal biodistribution of Zevalin was confirmed in all 4 patients during the imaging phase. No Zevalin-avid lesions was noted in one patient. There was faint visualization of some of the known lesions (by Ga-67 SPECT, CT or F-18 FDG PET) in the axilla and abdomen in 2 of the 4 patients. Intense Zevalin-uptake sites were identified in the supraclavicular, infraclavicular, mediastinal, hepatic and abdominal lymphatic chains in another patient. Imaging results and treatment responses are shown in the following table:
Patient Response Prior ASCT In-111 Zevalin-avidity Clinical 1 Yes none PD 2 No faint, right axilla PD 3 Yes very faint, abdomen NC 4 No intense NC
Treatment was well tolerated with hematologic toxicity similar to those observed in NHL patients. Our preliminary results suggest that RIT targeting reactive B cells in classical HL is feasible and safe. Future studies should incorporate pretreatment evaluation of a selected lymph node by fine needle aspiration to determine the fraction of reactive B cells in the microenvironment prior to treatment with RIT targeting CD20.
Dichotomy of All-Trans Retinoic Acid Inducing Signals for Adult T-Cell Leukemia.
Authors: Maeda Yasuhiro , Yamaguchi Terufumi , Hijikata Yasuki , Morita Yasuyoshi , Hirase Chikara , Takai Syunsuke , Miyatake Jun-ichi , Matsuda Mitsuhiro , Kanamaru Akihisa 
Published: April 2020

Abstract
We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-κB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax or pol mRNA) using the real time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT was inhibitory of proviral DNA but not NF-kB transcriptional activity and sIL-2R on HTLV-1, however ATRA was inhibitory of NF-kB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease of sIL-2R induced by ATRA may be caused by the actions of a NF-kB inhibitor acting on the NF-kB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-kB inhibitor and as a RT inhibitor.
Chemosensitization of Drug-Resistant Ramos B-NHL to Drug-Induced Apoptosis: YY1 Expression Is Decreased in Response to Cytoskeletal-Interacting Drugs.
Authors: Neshat Mehran , Jazirehi Ali R. , Bonavida Benjamin 
Published: April 2020

Abstract
The transcription factor Yin Yang 1 (YY1) regulates cellular differentiation, hematopoiesis, response to apoptotic stimuli, pathogenesis of cancer and its increased expression is associated with inhibition of differentiation of progenitor cells. We and others have previously shown that expression levels of YY1 also correlate with drug sensitivity in cancer cells. A comparison between the wild type (wt) Ramos, with the recently generated rituximab-resistant Ramos (Ramos RR) clones, revealed that, unlike wt Ramos, Ramos RR1 cannot be chemosensitized by rituximab and exhibited higher drug resistance. Further, there was enhanced YY1 expression in Ramos RR1. We hypothesized that overexpression of YY1 may be, in part, responsible for drug-resistance in Ramos RR1 and its inhibition can reverse resistance. This study investigated whether the heightened expression of YY1 in Ramos RR1 cells can be reversed by a panel of drugs used in combination. Ramos and Ramos RR1 cells were treated with vincristine, VP-16, CDDP, and ADR, and the NF-κB inhibitors Bortezomib and DHMEQ. Treatment of Ramos RR1 with the NF-κB inhibitor, in combination with any of the above chemotherapeutic drugs, reversed the acquired drug-resistance and synergy was achieved. Noteworthy, in Ramos RR1 cells, only vincristine (or in combination with NF-κB inhibitors) significantly abrogated or diminished YY1 expression. Similarly, in the prostatic cell line PC-3, 2-methoxyestradiol, another cytoskeletal interacting drug, resulted in marked reduction of YY1 expression level and activity (assessed by a luciferase reporter assay). These results suggest that YY1 overexpression may regulate the resistance of B-NHL to a selected group of drugs but not all drugs. The studies also suggest that agents that can modulate YY1 expression/activity may be potential therapeutics when used in combination with chemotherapeutic drugs in the treatment of drug and rituximab-resistant B-NHL. Currently, we are examining potential mechanisms that underlie the downregulation of YY1 expression by vincristine and 2-methoxyestradiol.
Suppression of Cell Growth and Induction of Apoptosis of HTLV-I-Infected T-Cell Lines and Primary ATL Cells by Galectin-9.
Authors: Okudaira Taeko , Tomita Mariko , Hirashima Mitsuomi , Mori Naoki 
Published: April 2020

Abstract
Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I), and remains incurable. Therefore, novel treatments are urgently needed. Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signaling pathways. The distribution of galectins is quite diverse, and their expression in various leukocytes has been observed. To determine whether expression of galectins in T cells correlates with HTLV-I infection, we surveyed a number of uninfected and HTLV-I-infected T-cell lines for galectin-3, -8, and -9 expression by RT-PCR. Expression of galectin-8 did not correlate with HTLV-I infection. Galectin-3 was abundantly expressed in HTLV-I-infected T-cell lines and primary ATL cells, but not in uninfected T-cell lines. In contrast, galectin-9 was abundantly expressed in uninfected T-cell lines and normal PBMCs, but not in HTLV-I-infected T-cell lines and primary ATL cells. HTLV-I transformed protein, Tax, did not affect the expression of galectin-3 and -9. It was previously shown that galectin-8 and -9 are proapoptotic proteins. We found that galectin-9 prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells compared with galectin-8. Galectin-9 induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, and Cdc25C, and apoptosis by reducing the expression of XIAP and c-IAP2. Most of these genes are known to be regulated by NF-κB, which plays a critical role in oncogenesis by HTLV-I. Galectin-9 suppressed phosphorylation of IκBα. Most importantly, treatment with galectin-9 reduced tumor formation from an HTLV-I-infected T-cell line, HUT-102, when these cells were inoculated s.c. into severe combined immunodeficient mice. Our results suggest that galectin-9 may be a new approach for management of ATL.