bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyses of Pokemon Protein Expression in Lymphoma Reveals Elevated Expression in Nodular Lymphocyte Predominant Hodgkin Lymphoma Compared to Classical Hodgkin Lymphoma.
Authors: Teruya-Feldstein Julie , Maeda Takahiro , Filatov Alexander , Pandolfi P.P. 
Published: April 2020

Abstract
Background: POKEMON (for POK, Erythroid, Myeloid ONtogenic factor) has recently been shown to be a novel proto-oncogene, playing a key role in cellular transformation and repression of ARF. Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Because these transgenic mice developed T-cell lymphoma we sought to expand our original screening analyses. We intially showed POKEMON expression in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and co-expression of BCL6 and POKMEON showed higher proliferation and predicted for better overall survival in DLBCL (Nature 433, 278–285). Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is another tumor that expresses BCL6 and shows localization to L&H tumor cells. We therefore sought to compare POKEMON protein expression in NLPHL and Classical Hodgkin Lymphoma (cHL) cases.
Design: Stains for POKEMON were performed with the anti-POKEMON hamster monoclonal antibody (clone 13E9). Sections of reactive human tonsil were stained as controls showing localization to squamous epithelium and reactive germinal centers as well as paracortical regions. For NLPHL, the cohort comprised of 19 males, 2 females; for cHL 16 males, 14 females. 20 NLPHL and 30 cHL tissue biopsies were stained using whole sections. Intensity and percent positivity of malignant L&H cells and Reed-Sternberg (RS) cells as well as surrounding reactive lymphocytes was scored. Expression in T-cell lymphomas was expanded to include a total of 84 cases analyzed by tissue microarray (TMA) that included: 8 ALCL (Anaplastic Large Cell Lymphoma), 11 AILT (Angioimmunoblastic T-cell Lymphoma), 17 T-ALL (T Lymphoblastic Lymphoma), 43 PTCL (Peripheral T-cell Lymphoma), 3 T/NK (Nasal type T/NK cell Lymphoma), and 2 PTCL, NOS (Not Otherwise Subclassified). Tumor cells in T-cell lymphomas and HL were scored and defined as 0 (negative), 1 (scattered &lt;50%, weak positive), and 2 (diffuse &gt;50%, strong positive) with a nuclear localization pattern.
Results: For NLPHL, 18/20 (90%) cases showed diffuse strong positivity in &gt;50% of malignant L&H tumor cells whereas in cHL cases, 6/30 (20%) cases showed diffuse strong positivity in &gt;50% of malignant RS tumor cells for POKEMON protein expression. In T-cell lymphomas, POKEMON expression was strongest in ALCL (6/8, 75%) and AILD (7/11, 74%) compared to the other subtypes. In contrast, BCL6 protein expression was positive in 12/20 (60%) cases which showed weak, scattered to diffuse strong positivity in L&H tumor cells and 1/30 (3%) with scattered weak reactivity in cHL malignant RS cells
Conclusion: POKEMON is co-expressed with BCL6 in malignant L&H tumor cells in NLPHL but not in cHL. Pokemon’s critical role in cellular transformation makes it an attractive target for therapeutic intervention in NLPHL.
Haplotype-Based Sequencing To Delineate the Associated HLA Class I Region for EBV Positive Hodgkin Lymphoma.
Authors: Niens Marijke , van den Berg Anke , Diepstra Arjan , Nolte Ilja M. , van der Steege Gerrit , Jarrett Ruth F. , Poppema Siebrand , te Meerman Gerard J. 
Published: April 2020

Abstract
Various studies have indicated that the human leukocyte antigen (HLA) region is associated with Hodgkin Lymphoma (HL). We recently demonstrated a specific association of the HLA class I region with Epstein-Barr virus (EBV) positive HL cases. The positively associated haplotype was characterized by alleles 126 and 284 of the consecutive microsatellite markers D6S265 and D6S510 while the negatively associated haplotype was characterized by alleles 130 and 302. Further fine mapping of this region is necessary to find the causative SNP(s). To select the most promising candidate SNPs for screening the total study population, known SNPs were sequenced in an individual homozygous for the positively associated haplotype and an individual homozygous for the negatively associated haplotype. Five SNPs (rs2530388, rs2523972, rs4713276, rs2256543, and rs6457110) that were selected on the basis of displaying different alleles in these two individuals were analysed in the total study population. The five SNPs showed significant association with the EBV-positive patient group, three of them revealed a stronger association than the previously identified associations (−log p difference = 1). These five SNPs were also analysed in a Scottish population, and four of them showed association in that population as well. The associated region was narrowed down from 310 kb in the original study to a region comprising less than 60 kb in the present study. Of the genes mapping to this candidate region, HLA-A represents the most interesting target because of its consistent expression in EBV positive HL cases and its ability to present EBV derived peptides to cytotoxic T cells.
Ocular Adnexal Lymphoma: A Clinicopathological Study of a Large Cohort of Patients with No Evidence for an Association with Chlamydia psittaci.
Authors: Rosado Manuel F. , Byrne Gerald E. , Ding Feying , Fields Keneth A. , Ruiz Phillip A. , Dubovy Sander R. , Walker Gale R. , Markoe Arnold , Izidore Lossos S. 
Published: April 2020

Abstract
Ocular adnexal lymphomas (OALs) represent 6% of all primary extranodal NHL. However, they are among the most common primary tumors occurring in the ocular adnexa (26%). The etiology of OALs and the reason for the predominance of extranodal marginal zone lymphoma (EMZL) in this anatomical location are unknown. Ferreri et. al (J Natl Cancer Inst2004; 96:586) recently reported the presence of C psittaci DNA in 80% of the analyzed Italian ocular adnexa EMZL cases. Herein, we reviewed our 14-year single institution experience in a large cohort of patients with primary OALs and examined the association with C psittaci infection in South Florida. Clinicopathological characteristics, response to therapy, systemic dissemination and patients’ survival were analyzed in 62 patients with primary OALs treated and followed-up at the Sylvester Comprehensive Cancer Center. EMZL was the most frequent histological subtype (89% of OALs). Majority of EMZL patients (84%) presented with stage IE, however only 16% had an advanced stage. All stage IE patients were treated with local radiotherapy, while patients with disseminated disease received systemic therapy with or without local irradiation. All but one EMZL patient achieved CR. During a median follow up of 52 months (range 3–153), the estimated 5-year OS and FFP were 96% (95% CI: 90 to 100%) and 79% (95% CI: 65 to 92%), respectively. During the follow-up, 22% of patients relapsed, mainly in extranodal sites and 4% transformed to diffuse large B-cell lymphoma. None of the patients exhibited local orbital failure in the radiation field. To analyze the association between C psittaci infection and OALs in our patient population, C psittaci touchdown enzyme time release-PCR was used in 57 tumor specimens. DNA was extracted from 49 specimens of EMZL of ocular adnexa, 8 specimens of non- EMZL of ocular adnexa and 2 specimens from patients with reactive ocular lymphoid hyperplasia. C psittaci DNA was not detected in any of the 57 tumor DNA samples positive for either beta-globin or ApoE DNA quality control amplicons, while control reactions using DNA prepared form C psittaci strain 6 BC yielded amplicon of expected size. It is thus possible that there is a regional variation in EMZL etiology and association with infection pathogens. Additional studies evaluating the association between C psittaci and EMZL of ocular adnexa in other geographical regions are granted.
Establishment of a Waldenstrom’s Macroglobulinemia Cell Line (BCWM.1) with Productive In Vivo Engraftment in SCID-hu Mice.
Authors: Santos Daniel Ditzel , Ho Allen W. , Tournilhac Olivier , Leleu Xavier , Hatjiharrisi Evdoxia , Xu Lian , Tassone Pierfrancesco , Neri Paola , Hunter Zachary , Chemaly Mariana A.Z. , Branagan Andrew , Manning Robert , Patterson Christopher , Adamia Sophia , Kriangkum Jitra , Kutok Jeffery L. , Pilarski Linda , Anderson Kenneth C. , Munshi Nikhil , Treon Steven P. 
Published: April 2020

Abstract
Waldenstrom’s Macroglobulinemia (WM) is incurable B-cell malignancy characterized by the infiltration of the bone marrow infiltration with lymphoplasmacytic cells (LPC) and the presence of an IgM monoclonal gammopathy. A significant impairment in understanding the biology and advancing therapeutics for WM has been the lack of a representative cell line and animal model. We therefore report on work accomplished in our laboratories in establishing the BWMC.1 cell line, which was derived from long term culture of CD19+ selected lymphoplasmacytic cells isolated from the bone marrow (BM) aspirate of a previously untreated 55-year-old female patient with IgMk secreting WM. BCWM.1 cells morphologically resembled LPC and had prominent nucleoli and ample cytoplasm by Wright-Giemsa staining, and were propagated in RPMI 1640 medium supplemented with 10% FBS. Phenotypic characterization by flow cytometric analysis demonstrated typical WM LPC characteristics: CD5−, CD10−, CD19+, CD20+, CD23+, CD27−, CD38+, CD138+, CD40+, CD52+, CD70+, CD117+, cIgM+, cIgG−, cIgA−, ck+, cl−. BCWM.1 cells also expressed the survival proteins APRIL and B-Lymphocyte Stimulator (B-LYS), and their receptors TACI, BCMA and BAFF-R. ELISA studies demonstrated secretion of IgMk in culture. Karyotypic and M-FISH studies did not demonstrate cytogenetic abnormalities. Molecular analysis of BCWM.1 cells confirmed clonality by determination of IgH rearrangements through FR1c/JHc amplification of genomic DNA. BCWM.1 cells were positive for LMP1 expression by histochemical staining and PCR analysis. Importantly, inoculation of BCWM.1 cells directly into the human BM milieu of SCID-hu mice resulted in engraftment of tumor cells and serum detection of human IgMk in four of five SCID-hu mice within two weeks. In contrast, subcutaneous injection of BCWM.1 cells in SCID mice did not lead to engraftment, suggesting a role for the human BM microenvironment in supporting the expansion of BCWM.1 cells. These studies therefore support the use of BCWM.1 cells as an appropriate model for the study of WM, which in conjunction with the SCID-hu mouse model may be used as a convenient model for studies focused on both the pathogenesis and development of targeted therapies for WM.
Strong BCL10 Nuclear Expression Identifies Gastric MALT Lymphomas That Do Not Respond to H. pylori Eradication.
Authors: Ye Hongtao , Gong Liping , Liu Hongxiang , Ruskone-Fourmestraux Agnes , de Jong Daphne , Pileri Stefano , Thiede Christian , Lavergne Anne , Boot Henk , Caletti Giancarlo , Wundisch Thomas , Molina Thierry , Taal Babs G. , Elena Sabattini , Neubauer Andreas , MacLennan Kenneth A. , Siebert Reiner , Remstein Ellen D. , Dogan Ahmet , Du Ming-Qing 
Published: April 2020

Abstract
Purpose: In a previous retrospective study, we have shown that 75% of gastric MALT lymphomas that did not respond to H. pylori eradication could be identified by detection of t(11;18)(q21;q21). The present study examined the value of t(1;14)(p22;q32) in prediction of the response of gastric MALT lymphomas to H. pylori eradication.
Patients and Methods: A total of 111 patients with H. pylori-positive gastric MALT lymphoma, who were treated by H. pylori eradication, were screened for BCL10 involved chromosome translocation by BCL10 immunohistochemistry, followed by interphase FISH and real-time quantitative reverse transcription PCR (qRT-PCR). The clinical presentation of 11 cases of MALT lymphoma including 6 from the stomach with known BCL10 involved chromosome translocation was reviewed.
Results: Of the 111 cases of gastric MALT lymphoma treated by H. pylori eradication, 75 including 35 from the complete regression group and 40 from the non-responsive group, had adequate specimens for BCL10 immunohistochemistry. Two cases showed strong BCL10 nuclear staining in virtually all tumor cells, similar to that seen in those with t(1;14)(p22;q32). Both were from the H. pylori eradication non-responsive group. Although interphase FISH failed to show evidence of BCL10 gene break or amplification, one case showed an IGH break. This case also showed a high level of BCL10 mRNA expression, compatible to that seen in MALT lymphoma with t(1;14)(p22;q32). 9 of the 11 cases with known BCL10 involved translocation were at stage IIE or above, with three showing agressive clinical presentations.
Conclusion: Gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14)(p22;q32) are mostly likely resistant to H. pylori eradication.
A Proteomic Approach to Discovery of Candidate Proteins Involved in the Transformation of Follicular Lymphoma.
Authors: Fan Guang , Zhong Yanping , Smith Cristina , Huang James , Braziel Rita 
Published: April 2020

Abstract
Background: Follicular lymphoma (FL) undergoes transformation to a high grade diffuse large B-cell lymphoma (tr-DLBCL) in about 50% of patients. During transformation, a more virulent subclone of tumor cells emerges, leading to a rapidly progressive clinical course and resistance to therapy. The identification of proteins involved in transformation is critical for understanding the mechanism of transformation and developing molecularly targeted therapy. In this study, we compared protein expression between grade 1- FL (G1-FL) and tr-DLBCL using 2D-gel electrophoresis and Western blot analysis.
Design: Frozen tissue and frozen cells were obtained from the Department of Pathology, Oregon Health and Science University tumor bank. The protein expression profiles of 3 G1-FL and 3 tr-DLBCL were compared using 2D-gel electrophoresis. Protein identification was done using a MALDI mass spectrometer. Frozen cells of an additional 11 non-paired GI-FL and 11 non-paired tr-DLBCL, and 2 pairs of G1-FL and tr-DLBCL specimens were used for Western blot confirmation of the initial 2D-gel findings.
Results: 2D-gel analysis and MALDI protein identification revealed 14 differentially expressed proteins between G1-FL and tr-DLBCL (figure 1), all of which are known to play important roles in cellular energy/metabolic pathways, signal transduction pathways, and protein and nuclear synthesis. The two most differentially expressed proteins on 2D-gel analysis were superoxide dismutase (MnSOD2) and growth factor receptor bound protein 2 (Grb2). Western blot analysis of MnSOD2 and Grb2 confirmed their relative over- or under-expression in frozen cells from multiple additional clinical lymphoma samples, including 2 paired- and 22 non-paired G1-FL and tr-DLBCL. Both 2D-gel analysis and Western Blot showed a significantly higher level of expression of MnSOD2 and a lower expression of Grb2 expression in tr-DLBCL (figure 2).
Summary: Using proteomic profiling, confirmed by Western blot analysis of clinical G1-FL and tr-DLBCL samples, we have confirmed 2 proteins (MnSOD2 and Grb2) that are expressed at significantly different levels in G1-FL and DLBCL. MnSOD2 is capable of protecting cells from reactive oxygen species and regulating signal transduction pathways to influence cell growth and apoptosis. Inhibition of MnSOD2 has been shown in studies of several cancer cell lines to render cancer cells more susceptible to apoptosis. Grb2 is a member of a critical signaling pathway leading to Ras activation in hematopoietic cells. Both proteins may play a critical role in FL transformation. These proteins have the potential to be therapeutic drug targets, diagnostic and/or prognostic markers, or biomarkers for monitoring therapeutic response.
Summary of Differentially Expressed Spots Summary of Differentially Expressed Spots Figure Figure
SELDI-TOF Identifies Specific Protein Patterns in Small Lymphocytic Lymphoma, Marginal Zone Lymphoma and Mantle Cell Lymphoma.
Authors: Rolland Delphine , Bouamrami Ali , Ballester Benoit , Grangeaud Samuel , Arlotto Marie , Paret Aurelie , Berger Francoise , Felman Pascale , Callet-Bauchu Evelyne , Coiffier Bertrand , Houlgatte Remi , Berger Francois , Thieblemont Catherine 
Published: April 2020

Abstract
Non-germinal centre small B-cell lymphomas represent a heterogeneous group of non-hodgkin lymphomas which most frequent histologic subtypes are small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). These three lymphoma entities have very different clinical outcomes but may be difficult to distinguish either histologically or clinically. We previously identified transcriptomic signatures specific of these 3 lymphoma subtypes. We further analyzed these lymphomas using Surface-Enhanced Laser Desorption/Ionisation Time of Flight (SELDI-TOF). A total of 58 tumors, including 20 SLL (all lymph nodes), 20 MZL (1 lymph node and 19 spleens) and 18 MCL (19 lymph nodes and 1 spleen) were analyzed. In addition, we included 7 controls obtained from traumatic normal spleens. The spectra were generated on weak cation exchange (CM10), strong anion exchange (Q10) and reversed-phase (H50) ProteinChip arrays. Protein patterns of all samples were comparatively analysed using two distinct strategies. We first used a binary recursive partitioning method with the Biomarker Pattern software (Ciphergen®), and second a hierarchical clustering method to visualized patterns of protein peaks completed with a supervised method (discriminating score) to point out individual peaks distinguishing the three histological subtypes (SLL, MZL and MCL). Spectra analyses revealed a very homogeneous protein patterns among all lymphoma samples. However specific SLL, MZL and MCL signatures based on 34 protein peaks with differential expression could be identified and allowed to classify 95% of the samples in their respective entity. SLL signature included 9 peaks, MZL signature 16 peaks and MCL signature 9 peaks. The binary recursive partitioning analysis was concordant but identified only the five most discriminant peaks. Further identification of the discriminating peaks is currently realized using SELDI-assisted purification. We are focusing on peaks at 9942 Da for SLL and at 11324 Da for MCL. Functional genomic studies can distinguish non-germinal small B-cell lymphomas at the transcriptomic level (our previous study) and at the proteomic level. This will provide new markers for diagnosis and potentially new therapeutic targets.
MLL Translocation Partners AF4, AF5q31, and ENL Associate in a Higher Order Protein Complex with CDK9 and Cyclin T1.
Authors: Lin Min , Cleary Michael L. 
Published: April 2020

Abstract
The Mixed Lineage Leukemia (MLL) gene is frequently involved in chromosomal translocations that cause acute leukemia. More than 40 different genes have been identified as MLL translocation partners, with the expression of corresponding MLL fusion proteins. The MLL protein has histone methyltransferase activity and is required for embryonic development and hematopoiesis. Several proteins have been demonstrated to associate with MLL in a macromolecular complex, which is believed to have chromatin remodeling function. However, the C-terminal SET domain of MLL, which carries the histone methyltransferase activity, is lost in all MLL fusion proteins, thus making the biochemical functions of the fusion proteins unclear. Moreover, the promiscuity of MLL translocation partners, most of them with no known functions, further complicates an understanding of MLL leukemogenic mechanisms. In this study, we purified a protein complex containing AF4, the most common MLL translocation partner, using a combination of conventional column chromatography and immunoaffinity techniques. The AF4 protein complex contains AF5q31 and ENL, two other MLL translocation partners, as well as CDK9 and Cyclin T1, a heterodimer that regulates transcriptional elongation. Gel filtration confirmed that these five proteins co-fractionate with an estimated overall size of 0.8 MDa. All protein-protein interactions were further confirmed by immunoprecipitation-western blotting from K562 cell nuclear extract. To investigate whether these protein-protein interactions are retained in corresponding MLL fusion proteins, immunoprecipitation-western blotting assays were carried out in human leukemia cell lines harboring MLL chromosomal translocations. We found that MLL-AF4, MLL-AF5q31, MLL-ENL and MLL-AF9 each associate with wild type AF4 complex components, including CDK9 and Cyclin T1. In contrast, MLL-AF6 does not associate with any of the AF4 complex components. We propose that the four nuclear MLL translocation partner proteins (AF4, AF5q31, ENL/AF9), whose translocations are found in over 75% of MLL leukemias, associate in a higher order protein complex with CDK9 and Cyclin T1 and thus function in part to regulate transcriptional elongation. The association of CDK9 and Cyclin T1 with the four MLL fusion proteins suggests a common leukemogenic mechanism that may involve transcriptional elongation, which we are currently investigating. Conversely, MLL-cytosolic fusions, e.g. MLL-AF6, appear to function independently of association with the AF4 protein complex, possibly through a homo-dimerization pathway.
Cdx4 Upregulates Hox Gene Expression and Generates Acute Myeloid Leukemia Alone and in Cooperation with Meis1a in a Murine Model.
Authors: Bansal Dimple , Scholl Claudia , Frohling Stefan , Mcdowell Elizabeth , Lee Benjamin H. , Dohner Konstanze , Ernst Patricia , Davidson Alan J. , Daley George Q. , Zon Leonard I. , Gilliland D. Gary , Huntly Brian J. 
Published: April 2020

Abstract
HOX genes have emerged as critical effectors of leukemogenesis, but the mechanisms that regulate their expression in leukemia are not well understood. Recent data suggest that the caudal homeobox transcription factors CDX1, 2 and 4, developmental regulators of HOX gene expression, may contribute to HOX gene dysregulation in leukemia. We report here that CDX4 is normally expressed in early hematopoietic progenitors, and is aberrantly expressed in~25% of AML patient samples. Cdx4 regulates Hox gene expression in the adult murine hematopoietic system, and upregulates Hox genes that are implicated in leukemogenesis. Furthermore, bone marrow progenitors that are retrovirally engineered to express Cdx4 serially replate in methylcellulose cultures, grow in liquid culture and generate a partially penetrant, long-latency acute myeloid leukemia (AML) in bone marrow transplant recipients. Co-expression of the Hox co-factor Meis1a accelerates the Cdx4 AML phenotype and renders it fully penetrant. Structure -function analysis demonstrates that leukemic transformation requires intact Cdx4 transactivation and DNA-binding domains, but not the Pbx co-factor interaction motif. Taken together, these data indicate that Cdx4 regulates Hox gene expression in adult hematopoiesis and may serve as an upstream regulator of Hox gene expression in the induction of acute leukemia. Inasmuch as many human leukemias show dysregulated expression of a spectrum of HOX family members, these collective findings also suggest a central role for CDX4 expression in the genesis of acute leukemia.