bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Fusion between ETV6 and NCOA2 Defines a New Entity of Acute Leukemia with Co-Expression of T-Cell and Myeloid Markers.
Authors: Strehl Sabine , Nebral Karin , König Margit , Harbott Jochen , Bielorai Bella , Struski Stephanie , Izraeli Shai , Haas Oskar A. 
Published: April 2020

Abstract
We have identified a novel recurrent translocation and the genes involved therein, which is associated with both lymphoid and myeloid acute leukemia. Fluorescence in situ hybridization (FISH) and molecular analyses revealed an in-frame fusion of ETV6 (alias TEL) and NCOA2 (alias TIF2) in six cases of childhood acute leukemia. ETV6 encodes an ets transcription repressor and is frequently involved in chromosome rearrangements with a multitude of partners in lymphoid and myeloid leukemia, and to a lesser extent also in solid tumors. NCOA2 is a member of the p160 family of nuclear receptor transcriptional coactivators (NRCoAs), which have a common domain structure with a conserved N-terminal bHLH-PAS domain, a centrally located (nuclear) receptor interaction domain (RID/NID), and a C-terminal transcriptional activation domain (AD2). NRCoAs typically display HAT activity and/or directly interact with CBP. In this context, NCOA2 also contains a C-terminal CBP-interaction domain (CID), and thus is a transcription factor that mediates transcriptional activation in a ligand-dependent fashion by a mechanism involving chromatin remodeling. As a result of the translocation the pointed (PNT) protein interaction domain of ETV6 is fused to the C-terminus of NCOA2 including the CBP and AD2 motifs. The same C-terminal domains of NCOA2 are also involved in the previously identified MOZ-NCOA2 fusion, which is generated by a inv(8)(p11q13). The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases, and the facts that MOZ-NCOA2 is transforming and that the reciprocal NCOA2-MOZ is not expressed, strongly suggest that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. Unlike in cases with a ETV6-RUNX1 fusion, which is frequently associated with a concurrent secondary deletion of the non-rearranged ETV6 allele, in all cases the second ETV6 and also one NCOA2 allele were retained and both genes were readily expressed. With respect to the immunophenotype, according to the European Group for the Immunological Characterization of Leukemias (EGIL), three of the cases were classified as T-ALL (one as T-I My+), two as biphenotypic leukemia (BAL), and one as AML with M1 phenotype. Nevertheless, all leukemias displayed aberrant co-expression of various T-cell and myeloid/NK markers, and were double-negative for CD4/CD8, suggesting transformation of early progenitors. In contrast to the MOZ-NCOA2 fusion, which is exclusively associated with AML, mostly of M4 and M5 subtype, the ETV6-NCOA2 fusion seems to define a new entity of acute leukemia with aberrant co-presence of T lymphoid and myeloid antigens.
Analysis of Loss of Heterozygosity in Adult Patients with De Novo Acute Myeloid Leukemia and Normal Karyotype.
Authors: Schon Christian , Bullinger Lars , Rucker Frank G. , Dohner Konstanze , Dohner Hartmut 
Published: April 2020

Abstract
A large proportion of acute myeloid leukemia (AML) exhibits a normal karyotype in which the underlying pathomechanisms still have to be determined. Novel techniques like arrayCGH or single nucleotide polymorphism (SNP) chip analysis allow the identification and characterization of molecular rearrangements at the sub-megabase level. Recently, the application of genome-wide SNP array technology revealed frequent uniparental disomy (UPD) in approximately 20% of AML suggesting that UPD represents a nonrandom event in leukemogenesis. Uniparental disomy is acquired by somatic recombination and therefore not accessible by conventional cytogenetic methods or arrayCGH. In this study we analyzed DNA from AML patients with normal karyotype for the presence of LOH. SNP analysis was performed on the Mapping 100k GeneChip (Affymetrix, Santa Clara, CA). DNA was extracted from paired samples of 56 de novo AML patients with normal karyotype at diagnosis and in complete remission, respectively. Signal intensity data were analyzed by the GCOS GeneChip analysis software and statistical analysis of SNP call data was performed by the dChipSNP software. In addition, standard mutation screening of the genes encoding NPM1, FLT3, CEBPA, MLL and NRAS was performed in all cases. Using the 100k SNP array, a mean SNP call rate of 98.2% was reached, resulting in &gt; 110,000 SNP genotype calls per sample. Signal intensity data analysis revealed submicroscopic chromosomal deletions resulting in hemizygosity in three patients. Patient 1 had a single 2 Mb deletion in chromosomal band 3p14.1, patient 2 had two small deletions affecting chromosome 12q23 and 12p13, the latter encompassing the ETV6 locus, and patient 3 had two small deletions within the long arm of chromosome 8. Besides these small chromosomal regions of copy number alterations, we found 4 large stretches of somatically acquired homozygosity without numeric alterations, affecting chromosome 6 (6p21 to 6 pter and 6q26 to 6 qter), chromosome 11 (11p12 to 11pter) and chromosome 13 (13q11 to 13qter). Noteworthy, in the case with uniparental disomy of chromosome 13, we could detect a homozygous FLT3-ITD mutation, supporting the findings that acquired isodisomy for chromosome 13 is common in AML, and associated with FLT3-ITD mutations (Griffiths et al., Leukemia, 2005). In summary, high resolution SNP assay technology in AML patients with normal karyotype allowed the identification of distinct chromosomal regions affected by UPD, supporting the postulated nonrandom mechanism of acquired mitotic recombination events in AML. Besides known chromosomal regions known to be affected by genomic aberrations in AML, we found additional submicroscopic chromosomal aberrations in cases with normal karyotype. Analysis of larger patient series will allow the identification of novel regions of interest harboring genes that might be involved in the pathogenesis of AML.
Gene Expression Differences between Low and High Stage Diffuse Large B Cell Lymphoma (DLBCL).
Authors: Roberts Robin A. , Rimsza Lisa M. , Staudt Louis , Rosenwald Andreas , Chan Wing-Chung , Dave Sandeep , Gascoyne Randy D. , Connors Joseph M. , Smeland Erlend B. , Muller-Hermelink H.K. , Campo Elias , Jaffe Elaine S. , Wilson Wyndham , Tan Bruce K. , Fisher Richard I. , Grogan Thomas M. , Miller Thomas P. 
Published: April 2020

Abstract
Low stage DLBCL patients have better prognosis than those with advanced disease. We searched for differences in gene expression between disease stages to find correlations with tumor stage as possible therapeutic targets. We used 2 microarray datasets from the Leukemia/Lymphoma Molecular Profiling Project containing nodal and extra-nodal de novo DLBCL samples on Lymphochip (LC), spotted arrays of ~7400 and Affymetrix arrays (Affy) of ~45,000 elements. The Affy dataset was a subset of the LC samples. LC elements were median-centered, log2 transformed; Affy elements were array-centered to a 500 average. We compared average gene expression in stage I vs. III/IV, looking for elements with &gt;2-fold differences between low and high stage, with p&lt;.05, excluding Affy elements with an average &lt;100. 35 stage I and 131 stage III/IV samples were analyzed with LC and 34 stage I and 118 stage III/IV samples with Affy. Differentially expressed genes were searched by NCBI Entrez and Stratagene PathwayArchitect software to find common pathways of regulation. From the LC data, 6 genes were identified as differentially expressed, 5 were higher in stage I, 1 was lower in stage I. For the Affy data, 29 genes were differentially expressed, 11 were higher in stage I, 18 were lower in stage I (Table 1). Differences were rarely &gt;3-fold. A subset of these genes, CTGF (connective tissue growth factor), FN1 (fibronectin), INHBA (activin), POSTN (periostin), THBS1 (thrombospondin), and BCL2, are coregulated and/or coregulatory. Many are expressed in the microenvironment and associated with fibrosis, wound healing and Th2 immune response. The presence of these genes at higher levels and their known associations implied a pathway of TGF-β signaling present mainly in the low stage DLBCL. Although TGF-β levels were not different between stages, differences in localization/activation of TGF-β could account for observed differences. In conclusion, there are a small number of stage-specific gene expression differences in DLBCL, and many of these relate to TGF-β signaling in the microenvironment. CTGF and FN1 were previously identified as key prognostic molecules in DLBCL (Rosenwald et al, NEJM 2002). These differences may relate to different prognoses between DLBCL stages and constitute therapeutic targets.
Genes Differentially Expressed by Stage higher in stage I higher in stage III/IV LC Affy LC Affy CTGF CTGF IGHM IBRDC2 (2 elements) SERPINA1 MYBPC1 HTR3A POSTN NCR3 BCL2 FN1 INHBA (2 elements) CRYM THBS1 EMP1 SIX1 KLHL14 MGC23911 PP1665 GPM6A (2 elements) FLJ33069 TUBB IgM rheum. factor RF-TT9 CD1C transcribed locus LOC150568 LOC346887 LOC283454 MGC17624 IMAGE:5311619 transcribed locus (2x)
Structural Profiles of p53 Gene Mutations Predict Clinical Outcome in Diffuse Large B-Cell Lymphoma: An International Collaborative Study.
Authors: Young Ken H. , Leory Karen , Møller Michael B. , Sánchez-Beato Margarita , Colleoni Gisele W.B. , Kerbauy Fabio R. , Koduru Prasad P.K. , Haioun Corinne , Gaulard Philippe , Piris Miguel A. , Campo Elias , Delabie Jan , Gascoyne Randy D. , Rosenwald Andreas , Ott German , Huang James , Braziel Rita M. , Jaffe Elaine S. , Staudt Louis M. , Wilson Wyndham H. , Kanehira Kazunori , Rehrauer William M. , Eickhoff Jens C. , Kahl Brad S. , Malter James S. , Chan Wing-Chung , Wisenburger Dennis D. , Greiner Timothy C. 
Published: April 2020

Abstract
Mutations of the p53 tumor suppressor gene have been associated with a poor clinical outcome in some series of diffuse large B-cell lymphoma (DLBCL). However, conflicting results have been reported in other studies. The purpose of this study was to analyze the p53 mutations in DLBCL from twelve centers, and to correlate the structural profiles of the mutations with clinical outcome. The p53 mutations were identified in 102 of 477 cases of DLBCL for a frequency of 21.4%. These included 92 missense mutations, 5 nonsense mutations, 4 deletions, and 1 insertion. The presence of any p53 mutation correlated with poor overall survival (OS; P=0.002). Sixty-two of 102 cases (61%) had mutations in the DNA binding domains of the p53 gene, and the mutations in the DNA-binding domains were found to be the most important predictor of poor OS (P&lt;0.001). In contrast, mutations in the non-DNA binding domains did not correlate with OS (P=0.158). The 5-year survival rate was 24% in patients with any p53 mutation (median survival=1.33 yr) and 19% of patients with the DNA-binding domain mutations (median survival=1.0 yr) compared to 41% for those with wild type p53 (wt-p53, median survival=4.5 yr). The complete remission rate was 57% in patients with any p53 mutation and 54% in patients with the DNA-binding domain mutations compared to 69% for those with wt-p53. Of the mutations in the DNA-binding domains, patients with mutations in the loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) and DNA minor binding groove motif (Loop L3, 22% of all mutations) had significantly decreased OS (P=0.002). In contrast, OS was not significantly decreased for patients with mutations in Loop L2 (18% of all mutations). Multivariate analysis confirmed that the International Prognostic Index, age, tumor size, serum lactate dehydrogenase, and mutations in the DNA binding motifs were independent predictors of OS. The p53 mutation profile was also found to stratify germinal center B-cell-like DLBCL, but not activated B-cell-like DLBCL, into molecularly distinct subsets with different clinical outcomes. This study demonstrates the importance of the mutational profile in the DNA binding domains of the p53 gene for predicting clinical outcome and refining current prognostic models including gene expression profiling in patients with DLBCL.
Prognostic Indices in Older DLBCL Patients Receiving R-CHOP: An Analysis of the U.S. Intergroup Study (E4494, CALGB 9793).
Authors: Advani R.H. , Chen H. , Habermann T.M. , Morrison V.A. , Weller E. , Fisher R.I. , Peterson B.A. , Gascoyne R.D. , Horning S.J. 
Published: April 2020

Abstract
Background: We reported that addition of rituximab (R) to chemotherapy significantly improves outcome in DLBCL patients (pt) &gt;60 years (JCO24:3121–27, 2006). Although the IPI is a robust clinical prognostic tool in DLBCL, Sehn et al (ASH 2005: abstract 492) reported that a revised (R) IPI more accurately predicted outcome in pt treated with rituximab-chemotherapy.
Methods: We evaluated outcomes of the Intergroup study with respect to the standard IPI, R-IPI, age-adjusted (aa) IPI for evaluable pt treated with R-CHOP alone or with maintenance rituximab. We further assessed a modified IPI (mIPI) using age ≥ 70 y as a cutoff rather than age 60 y.
Results: The 267 pt in this analysis were followed for a median of 4 y. Pt characteristics were: age &gt; 70 (48%) (median=69), male 52%, stage III/IV 75%, &gt;1 EN site 30%, LDH elevated 60%, PS ≥2 15%. On univariate analysis all of these characteristics were significant for 3 y failure-free survival (FFS) and overall survival (OS). The IPI provided additional discrimination of risk compared to the R-IPI with significant differences in FFS and OS for 3 vs 4–5 factors. The aa-IPI defined relatively few pt as low or high risk. The impact of age was studied using a cut-off of 70 years in a modified IPI, yielding 4 risk groups as shown below.
Conclusions: For pt ≥ 60 treated with rituximab-chemotherapy the distinction between 3 vs 4,5 factors in the IPI was significant.The IPI also provided additional discrimination of risk compared to the R-IPI. In this older group of pt, use of an age cutoff ≥70 y placed more patients in the low risk category. It is of interest to apply the mIPI in other datasets with DLBCL pt &gt;60 y.
Group # Factors # Pt % 3y FFS* % 3y OS* *All risk groups significantly different; logrank p &lt; 0.001 **95 % CI: FFS (0.46,0.66), OS (0.58,0.78) ***95 % CI: FFS (0.21,0.45), OS (0.31,0.55) L: Low, LI: Low Intermediate, HI: High Intermediate, H; High IPI L 0–1 12 78 83 LI 2 28 70 80 HI 3 33 56** 68** H 4–5 37 33*** 43*** R-IPI Very Good 0 0 - - Good 1–2 40 72 81 Poor 3–5 60 46 57 aa-IPI L 0 12 78 83 LI 1 35 68 78 HI 2 44 47 59 H 3 9 31 35 mIPI (age ≥ 70) L 0–1 27 77 86 LI 2 28 62 74 HI 3 29 47 58 H 4–5 16 28 36
A Large Scale Evaluation of Genetic Variation in Immune and Inflammation Genes and Risk of Non-Hodgkin Lymphoma.
Authors: Cerhan James R. , Ansell Stephen M. , Fredericksen Zachary S. , Kay Neil E. , Liebow Mark , Call Timothy G. , Dogan Ahmet , Cunningham Julie M. , Liu Wen , Macon William R. , Witzig Thomas E. , Habermann Thomas M. , Slager Susan L. 
Published: April 2020

Abstract
Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and may develop in the setting of inflammation and immune dysfunction. Small scale evaluations have suggested that common genetic variation in candidate genes related to immune function may predispose to the development of NHL. Here we report a comprehensive analysis of variants within genes associated with immunity and inflammation and risk of NHL.
Methods: We used ParAllele’s Immune and Inflammation panel of 9,412 single nucleotide polymorphisms (SNPs) from 1,450 immune/inflammation genes as a discovery tool in a clinic-based study of 458 NHL cases and 484 frequency matched controls seen at the Mayo Clinic from 2002–2005. The panel included 537 coding non-synonymous SNPs (nsSNPs), with the remainder of the SNPs selected as tags from HapMap (tagSNPs) to provide coverage of the candidate genes (r2 = 0.8 and minor allele frequency &gt;0.05). To assess the association of individual SNPs with risk of NHL, we calculated Odds Ratios (ORs) and 95% confidence intervals, adjusted for age and gender. The most prevalent homozygous genotype was used as the reference group, and each polymorphism was modeled individually as having a log-additive effect in the regression model. Associations between haplotypes from each gene and the risk of NHL were calculated using a score test implemented in HAPLO.SCORE. We also modeled the main effects for all independent (r2 &lt;0.25) SNPs from a gene in a multivariate logistic regression model.
Results: The mean age at diagnosis was 60 years for cases and 58% were male; in controls the mean age at enrollment was 61.6 years and 55% were male. In the gene analyses, the strongest findings (p≤0.001 from multiple SNP logistic regression or haplotype analysis) were for cAMP responsive element binding protein 1 (CREB1; p=0.0004), fibrinogen alpha chain (FGA; p=0.0006), TNF receptor-associated factor 1 (TRAF1; p=0.001), dual specificity phosphatase 2 (DUSP2; p=0.001), and fibrinogen gamma chain (FGG; p=0.001). In the nsSNP analyses, the strongest findings (p≤0.01) were for integrin β3 (ITGB3) L59P (OR=0.64, 0.50–0.83), Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) H328R (OR=0.72, 0.57–0.91), transporter 2, ATP-binding cassette (TAP2) T665A (OR=1.32, 1.07–1.63), HLA-B associated transcript 2 (BAT2) V1895L (OR=0.60, 0.42–0.85), and complement component 7 (C7) T587P (OR=1.39, 1.07–1.80).
Conclusions. Our results suggest that genetic variability in genes associated with antigen processing (CREB1 and TAP2), lymphocyte trafficking (B3GNT3), immune activation (TRAF1, BAT2), complement and coagulation pathways (FGA, FGG, ITGB3, C7), and MAPK signaling (DUSP2) may be important in the etiology of NHL, and should be pursued in replication studies.
The Focal Adhesion Kinase (FAK) Inhibitor TAE226 Exhibits In Vitro and In Vivo Activity Against Multiple Myeloma.
Authors: Sharkey Janelle , Yeh Sung Lin , Spencer Andrew 
Published: April 2020

Abstract
Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated B-cells characterized by both de novo and acquired resistance to presently available cytotoxic therapeutic agents. TAE226 (Novartis) is a potent and specific inhibitor of focal adhesion kinase (FAK) phosphorylation that also has the capacity to inhibit IGF1-R at sub-micromolar concentrations. FAK inhibition has been shown to abrogate intra-cellular phosphorylation of both ERK and AKT and to have anti-tumor effects in murine solid-tumor xenografts. Based on these data we have undertaken a pre-clinical evaluation of TAE226 as a potential therapeutic for MM. Eight genetically heterogeneous human myeloma cell lines (HMCL) (KMS11, KMS12, JIM1, LP-1, U266, RPMI8226, NCI H929, OPM2) were evaluated by MTS assay following exposure to TAE226 at various concentrations for 24 to 72 hours. All HMCL displayed reductions in viability (45% to 100% at 72 hours with 10μM) that were dose and time-dependent, with the range of effective TAE226 concentration being 1 – 10μM depending on cell type. Under standard culture conditions 5μM TAE226 was markedly cytostatic with complete inhibition of cellular proliferation observed over a 72 hour time period and with cell viability at 72 hours based on tryphan blue exclusion in the range of 40 – 90%. Four HMCL with modest (KMS11/U266) or high (LP-&, OPM2) TAE226 sensitivity were further using 5μM TAE226 for 48 hours. AnnexinV expression confirmed apoptosis induction while PhosFlow measurement of p44/42 MAPK confirmed abrogation of intra-cellular ERK phosphorylation - relative reduction following TAE226 compared to untreated controls of 11% KMS-11, 13% U266, 35% OPM2 and 64% LP-1. The induction of synergistic killing of NCI H929 was observed by combining TAE226 (1μM) with sub-lethal concentrations of either bortezomib (5nM) (synergism quotient (SQ) = 1.5) or adriamycin (10μg/ml) (SQ = 1.4) with the scheduling of TAE226 prior to drug partner superior to the reverse order (SQ both = 1.2) of administration. Primary MM cells from patients (n = 7) with advanced relapsed disease were treated after appropriate informed consent. Cell killing as determined by propidium iodide expression varied widely but with a clear dose-dependency – 5μM median 11%, range 0% – 47%; 10μM median 14%, range 1% – 61%; and, 20μM median 31%, range 9% – 67%. Finally, we tested TAE226 in the 5T33 murine model of systemic myelomatosis. C57BL/KaLwRiJ hosts were treated with TAE226 30mg/kg (n = 9) or vehicle (n = 9) for 14 days from day +7. Median time to hind limb paralysis post-treatment was prolonged in the TAE226 group compared to vehicle treated animals, 16 days vs 9 days, respectively (p = 0.06, Log Rank). We conclude based on these encouraging preliminary data that TAE226 warrants further evaluation as a potential therapeutic for MM.
An International Multi-Center Microarray Study for the Molecular Classification of Leukemia Identifies Novel Sub-Groupings in MDS Overlapping with AML.
Authors: Mills Ken I. , Haferlach Torsten , Hernandez Jesus M. , Hofmann Wolf-Karsten , Kohlmann Alexander , Williams Mickey , Wieczorek Lothar 
Published: April 2020

Abstract
Microarrays can identify robust gene expression signatures associated with distinct sub-classes of paediatric and adult leukemias. Recently, the MILE (Microarray Innovations in LEukemia) study has analysed 1901 expression profiles from retrospective samples in 11 centres (ELN: 7, USA: 3, Singapore: 1). MILE has compared the microarray classification accuracy of 16 acute and chronic leukaemia subclasses, MDS, and non-leukaemia as control group, to routine diagnostic workup. The achieved cross-validation accuracy was very high for the leukaemia subclasses: ~96%.
Included in the study were 175 samples diagnosed as MDS, however, only 49.1% of these samples were correctly called as MDS from their underlying gene expression profiles. The remainder were approximately equally split between a call of “non-leukaemia” (24%) and “AML” (24.6%). A further sub-division of MDS samples called “AML”: 81% called as “AML with normal or other cytogenetics”; and the remainder as “AML with complex cytogenetics”.
MDS is a heterogeneous group of disorders with a wide range in blast cell count, cytogenetics and number of cytopenias. Our analysis showed that neither study centre nor age were a factor in differentiating between “MDS”, “AML” or “non-leukaemia”. However, WHO classification was highly correlated with the microarray classification result; specifically RAEB(I or II) was associated with “AML” call (p &lt; 0.0001). RA/RARS was highly correlated with “MDS” or “non-leukaemia” calls. Furthermore, IPSS was significantly correlated with call (p&gt;0.0001): 65% of patients with an IPSS score of Int-2 or above were classified as “AML”. Examination of the individual components of the IPSS showed that two patients classified as “AML” had a blast count of &gt;20%, under the WHO definition these would be defined as AML and were excluded. Individually, the blast, karyotype and cytopenia contributions were highly significant (p&lt;0.0001, &lt;0.013 and &lt;0.0001 respectively) when comparing “AML”, “MDS” and “non-leukemia” calls. All the “non-leukemia” patients had &lt;10% blasts, with 85% (34/40) having a cytogenetic score of 0 (Normal or Good (1 of: -Y, del(5q), del(20q))) and 82.5% having only 0 or 1 cytopenias. In contrast, 45% of the “AML” samples had between 11 & 20% blasts, 32% with intermediate (0.5) or poor/complex (1) cytogenetic score and 79% had 2 or 3 cytopenias. Furthermore, survival data was available for 122 of the diagnosed MDS patients and showed that MDS patients called “AML” had a trend towards shorter survival (2P=0.2) than those called “MDS” or “non-leukaemia”. These analyses, in combination with gene expression signatures, may contribute to a redefinition of MDS classifications.