bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Profiling of Paired Pre- and Post-Prednisolone (PRED) BM Samples from Childhood ALL Identifies Robust Signatures for PRED Response and Eventual Outcome.
Authors: Lu Yi , Liu Huiqing , Xu Ying , Lin Koh Pei , Hany Ariffin , Wong Limsoon , Yeoh Allen Eng Juh 
Published: October 2019

Abstract
Early response to therapy is the most important prognostic factor for childhood ALL. CCG investigators have shown that Day-7 and Day-14 BM blast counts were prognostically important although there is great inter-observer variability. BFM group have shown that day 8 prednisolone (PRED) response is highly predictive of the treatment outcome. While gene expression profiling (GEP) of diagnostic marrow can discern a pattern of PRED sensitivity as determined by in vitro MTT assay, the accuracy was low at only 70%. We hypothesized that changes in global GEP after therapy have a higher likelihood to predict response as the signatures of sensitivity and resistance may be unmasked during the therapy. We prospectively studied the changes in GEP using Affymetrix HG-U133A or Plus 2 chips on paired BM samples before and after 7-day course of PRED and one dose IT MTX in 58 patients with newly diagnosed or relapsed ALL. Unsupervised hierarchical clustering revealed that pre- and post- PRED samples in the patients still tended to cluster together, indicating that expression profiles of molecular subgroups were still most important. To remove intrinsic influence of molecular subtypes and identify potential signatures independent of genetic abnormalities, we subtracted Day-0 GEP from its paired Day-8 profile and retained probe sets with significant changes (≥ 10-fold). To avoid the ambiguity of variation in BM blast counting at Day-8, we divided the samples into a stringently reproducible group where “Good” PRED response was defined as that Day-8 blast count in PBL < 109/L and BM lymphoblasts ≤ 30% (n=16). “Poor” response was when Day 8 PBL ≥ 109/L (n=11). This stringently reproducible group (n=27) formed the training group to help define a distinct signature while the rest (n=31 pairs) were used as a blinded test set. 54 and 19 discriminating genes were identified by 2 independent statistical methods respectively, and an integrated predictor model was constructed based on shortlisted entries. This model predicted the PRED response with 100% accuracy for the training set using the leave-one-out cross validation but was less accurate in predicting the BM blast count in blinded test set. But intriguingly, in the blinded test set, this model predicted correctly 19 out of 21 reliable “Good” PRED responses are in CCR (91%), while among 8 predicted as “Poor” responses, only 2 are in CCR (25%). This suggests that as gene expression profiling as early as day 8 of PRED could discern the beginning of leukaemia cell death even before morphological changes are discernable and is highly correlated to eventual outcome. In conclusion, we have shown that analyses on the relative changes of gene expression profile can identify real genetic signatures indicating the sensitivity to PRED administration which is highly correlated with outcome.
Mantle Cell Lymphoma: An Epigenetic Disease of Cyclin D1 Deregulation Involving Nucleophosmin, CTCF and Small RNA’s.
Authors: Epner Elliot , Jing Huang , Jin Wang , Fleming W.H. 
Published: October 2019

Abstract
Translocations involving the immunoglobulin heavy chain gene locus (IgH) are common in B cell malignancies. The molecular mechanisms of long distance gene activation by IgH regulatory elements in B cell malignancies are unknown. One common target gene is cyclin D1, which is deregulated in most patients with mantle cell lymphoma (MCL) and 20–30% of patients with multiple myeloma (MM). Cyclin D1 is known not to be expressed in normal lymphocytes, yet is deregulated by IgH translocations and insertions. Chromatin immunoprecipitation (ChIP) assays demonstrated the presence of the CCCTC-binding factor (CTCF) at both the cyclin D1 promoter and 3′ IgH regulatory regions only in cyclin D1 expressing malignant B cell lines containing IgH translocations or insertions. The nucleolar protein nucleophosmin (NPM), a newly identified CTCF interaction partner, exhibited a similar distribution in ChIP assays. Combined FISH/immunofluorescence assays in MCL cell lines and patient samples have demonstrated the presence of the cyclin D1/IgH translocated locus at the nucleolus specifically in cells with the t(11;14). Short hairpin (Sh) RNA mediated NPM knockdown results in a specific growth arrest only in cells with translocated chromosomes. Cell growth in variant MCL cells and B lymphocytes is not altered. The presence of small RNA’s and binding of the protein Dicer at the translocation breakpoint has been demonstrated. ShRNA knockdown of dicer results in significant reduction of cyclin D1 protein in MCL cells. Tethering of the cyclin D1 promoter to the 3′ IgH regulatory regions at the nucleolar membrane by CTCF/nucleophosmin provides a mechanism for spatial juxtaposition of the cyclin D1 promoter and 3′ IgH regulatory elements that facilitates deregulated expression of the cyclin D1 gene. These results also demonstrate the participation of small RNA’s and the RNA interference pathway in the deregulated expression of cyclin D1 in MCL.
Fyn Upregulation Is a Novel ROS-Dependent Mechanism Controlling CML Growth, Progression and Imatinib Resistance.
Authors: Chandra Joya , Amin Hesham M. , Howard Adrienne , Miller Claudia P. , Lin Quan , Ban Kechen 
Published: October 2019

Abstract
The BCR/ABL kinase alters the oxidative environment in chronic myelogenous leukemia (CML) cells, but the consequences of the increased reactive oxygen species (ROS) levels on signaling pathways remain unknown. Increased intracellular peroxides in BCR/ABL expressing cells have been linked to DNA damage, which may promote blast crisis in CML. We report that Fyn is a BCR/ABL target that is upregulated in an oxidant- sensitive manner. Cells overexpressing BCR/ABL display a four-fold upregulation of Fyn protein, which is blocked by chemical antioxidants. This increase in Fyn directs proliferative and survival signals since knockdown of Fyn using shRNA slows leukemia cell growth by 50% both in vitro and in vivo, inhibits clonogenic growth by 45% and leads to increased sensitivity to imatinib. Jak2 inhibition prevents Fyn protein upregulation, suggesting that Jak2 is upstream of Fyn, and we indeed find that Jak2 levels are increased in BCR/ABL expressing cells. In a cohort of CML patients Fyn expression was significantly increased in blastic phase CML samples as compared to chronic phase, confirming the clinical relevance of Fyn upregulation. Collectively, these results demonstrate that oxidant-dependent, Jak2-dependent upregulation of Fyn is a novel alteration in CML that is critical for cell growth and imatinib resistance.
Human T-Cell Leukemia Virus Type I Tax Activates CD69 Gene Expression.
Authors: Ishikawa Chie , Okudaira Taeko , Nakazato Tetsuro , Tomita Mariko , Mori Naoki 
Published: October 2019

Abstract
The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is etiologically linked to the genesis of adult T-cell leukemia (ATL). Emerging evidence suggests that the pathogenicity of ATL involves suppression of the overall immune response, although the underlying mechanism remains unclear. In this study, we demonstrated that HTLV-I transactivator Tax induces the aberrant expression of CD69, an early leukocyte activation molecule that plays an important role in downregulation of the immune response. In a panel of HTLV-I-infected T-cell lines, CD69 expression was highly elevated compared to HTLV-I-negative T-cell lines at both mRNA and protein levels. Furthermore, CD69 expression correlated with Tax expression. Peripheral blood mononuclear cells from ATL patients also showed an increased expression of CD69 compared with controls. In vitro infection of a T-cell line with HTLV-I was associated with CD69 expression in conjunction with the increasing Tax expression. Expression of CD69 was dependent upon Tax expression in the inducible Tax-expressing cell line JPX-9. Tax transactivated the CD69 gene promoter in a transient transfection assay. Using Tax mutants and dominant negative mutants of IκBs, IKKs, NIK, and CREB, we demonstrated that Tax-induced CD69 expression required the NF-κB and CREB signaling pathways. A series of deletion and mutation analyses of the CD69 gene promoter indicated that two NF-κB, two EGR, and a CRE sequences were critical for Tax transactivation. Electrophoretic mobility shift assay showed the formation of specific protein-DNA complexes in HTLV-I-infected T-cell lines. These results suggest that Tax directly transactivated CD69 gene expression, through multiple cis-acting elements and by the interplay of transcription factors of the NF-κB, EGR, and CREB families. Tax-induced CD69 expression may be involved in immune suppression in ATL.
Clinical Relevance of Complex Chromosomal Aberrations in Bone Marrow Cells of 107 Children with ETV6/RUNX1 Positive Acute Lymphoblastic Leukemia (ALL).
Authors: Zemanova Zuzana , Michalova Kyra , Babicka Libuse , Pavlistova Lenka , Jarosova Marie , Holzerova Milena , Oltova Alexandra , Hruba Martina , Muzikova Katerina , Zuna Jan , Trka Jan , Mihal Vladimir , Sterba Jiri , Formankova Renata , Sedlacek Petr , Vrzalova Alena , Stary Jan 
Published: October 2019

Abstract
Cryptic translocation t(12;21)(p13;q22) which give origin to the ETV6/RUNX1 hybrid gene can be found by I-FISH in approximately 20–25% of children with B precursor ALL as the most frequent specific aberration. This translocation is generally associated with good outcome. Despite of its favorable prognostic value, late relapses may occur within this group of patients. One of the reasons could be the high instability of the genome of leukemic cells, which is manifested at the chromosomal level by additional aberrations and/or complex chromosomal rearrangements. The aim of the study was to evaluate the significance of the additional chromosomal aberrations for prognosis of children with ETV6/RUNX1 positive ALL.
For the assessment of ETV6/RUNX1 fusion gene RT-PCR and/or double target interphase FISH with locus-specific probe (Abbott-Vysis, Des Plaines, Illinois, USA) were used (200 interphase nuclei analyzed, cut-off level 2.5% tested on controls, standard deviation ≤0.5%). Karyotypes were analyzed by conventional and molecular cytogenetic methods. Structural and/or complex chromosomal aberration were verified by FISH with whole chromosome painting probes (Cambio, Cambridge, UK) and/or by mFISH with the "24XCyte" probe kit (MetaSystems GmbH, Altlussheim, Germany).
We performed prospective and retrospective study of 107 children with ALL and ETV6/RUNX1 fusion gene detected by RT-PCR and/or I-FISH. Patients were diagnosed between 1995 and 2006, age ranged between 15 months and 16.9 years (median 4.2 years). Relapse appeared in 19 children (17.8%), four of them died. In 64 children (59.8%) we found besides t(12;21)(p13;q22) additional chromosomal aberrations, the most frequently trisomy or tetrasomy of chromosome 21 (20 cases), deletion of non-translocated ETV6 allele (24 cases), deletion of 6q (7 cases) and/or rearrangements of the long arm of chromosome X (6 cases). Complex karyotypes were identified in 38 children (35.5%). In twelve of them variant translocations of chromosomes 12 and 21 with other partners were observed. Event-free survival (EFS) was significantly shorter in patients with additional structural and/or complex aberrations in ETV6/RUNX1 positive cells (p=0.01).
In our cohort complex karyotypes indicated poor prognosis. Finding of complex chromosomal aberrations in leukemic cells is accompanied by higher risk of relapse even in those cases where the prognostically positive aberration is primarily present.
IgA and IgG Hypogammaglobulinemia Are Associated with Mutations in the APRIL/BLYS Receptor TACI in Waldenstrom’s Macroglobulinemia (WM).
Authors: Hunter Zachary , Leleu Xavier , Hatjiharissi Evdoxia , Santos Daniel , Xu Lian , Ho Alan , Bakthavachalam Vinod , Moreau Anne-Sophie , O’Connor Kelly , Soumerai Jacob , Patterson Christopher , Ghobrial Irene , Hamilton Susanna , Verselis Sigitas , Fox Edward , Treon Steven 
Published: October 2019

Abstract
IgA and IgG hypogammaglobulinemia are a common finding in patients with WM which may contribute to recurrent infections seen in up to half of WM patients. The etiology for this finding remains unclear. As part of these studies, we investigated the prevalence and genetic basis for IgA and IgG hypogammaglobulinemia among 89 previously untreated patients with the clinicopathological diagnosis of WM. Their median IgM was 2,980 (180–12,400) mg/dl, median BM involvement was 35% (5%–95%) and median B2M was 2.7 (1.4–13.7 mg/dL). Fifty-six (63%) and 66 (74%) of these patients demonstrated IgG (<700 mg/dL) and IgA (<70 mg/dL) hypogammaglobulinemia, respectively. Importantly, no correlation was seen between serum IgG and IgA levels and BM disease involvement, suggesting no direct impact of disease involvement on the production of uninvolved immunoglobulins. Given these findings, we undertook extensive germline and somatic sequence studies to determine if mutations existed within the APRIL/BLYS receptor TACI, which commonly is mutated in patients with Common Variable Immunodeficiency Disorder (CVID). Six of 29 (21%) sequenced patients displayed variants within TACI, which were present in both tumor cells (n=6) and germline (n=5). Importantly, patients displaying variants in TACI demonstrated significantly lower serum IgG (280 vs. 676 mg/dL; p=0.0009) and IgA (20 vs. 41 mg/dL; p=0.0006) levels versus patients without TACI variants. Lastly, sequence analysis of APRIL, BLYS as well as the TACI downstream TRAF proteins have led to detection of numerous variants which may further account for hypogammaglobulinemia among patients with normal TACI expression. These data suggest that aberrations in TACI signaling may account for IgG and IgA hypogammaglobulinemia in WM, akin to patients with CVID. Moreover, mutations within TACI signaling may have pathological implications for WM since a 300 fold increased incidence of lymphoma has been observed among CVID patients. The impact of TACI mutations on pathogenesis of WM is currently under investigation in our laboratory.
The Prognosis of Karyotypic Subgroups in Pediatric Acute Myeloid Leukemia Depends on the Alterations of KIT, MLL and FLT3 Genes: A Report from Japanese Childhood AML Cooperative Study Group.
Authors: Shimada Akira , Taki Tomohiko , Tabuchi Ken , Hanada Ryoji , Tawa Akio , Tsuchida Masahiro , Horibe Keizo , Tsukimoto Ichiro , Hayashi Yasuhide 
Published: October 2019

Abstract
Karyotypic abnormalities are associated with a prognosis of acute myeloid leukemia (AML). However, there are some patients who had poor prognosis among patients with the same karyotypic abnormalities. Recently, it is revealed that alterations of the genes including tyrosine kinases, lead to poor prognosis in AML. Genetic alterations associated with a poor prognosis remain to be clarified in karytotypic subgroups of AML. We performed the mutation analysis of FLT3, MLL, KIT, RAS and NPM in 158 pediatric AML patients who were enrolled in Japanese Childhood AML Cooperative Treatment Protocol, AML99, including 33 with normal karyotype, 46 with t(8;21), 7 with inv(16), 20 with 11q23 translocations, 13 with t(15;17), 10 with Down syndrome (DS) FAB-M7 and 29 other karyotypic abnormalities. In the 33 patients with normal karyotype, 9 FLT3-internal tandem duplication (ITD), 2 FLT3-D835 mutation (D835Mt), 8 MLL-partial tandem duplication (PTD), 2 KIT, 2 NRAS and 3 KRAS mutations were identified. FLT3-ITD and MLL-PTD were associated with a poor prognosis. Notably, NPM gene mutation was not identified in these patients. In the 46 patients with t(8;21), 2 FLT3-ITD, 1 D835Mt, 4 MLL-PTD, 8 KIT, 4 NRAS and 5 KRAS mutations were found. KIT mutations were associated with a poor prognosis. In the 7 patients with inv(16), 2 FLT3-D835Mt and 1 KIT mutations were identified. Only one patient with KIT mutation relapsed. In the 20 patients with 11q23 translocations, 1 D835Mt and 5 MLL-PTD were identified. MLL-PTD was associated with a poor prognosis in patients with 11q23 translocations. In the 13 patients with t(15;17), 3 FLT3-ITD and 3 D835Mt were found. FLT3-ITD was not associated with a poor prognosis. In the 10 patients with DS-M7, KIT and KRAS mutations were found in each one patient, showing no prognostic significance. In the 29 patients with other karyotypic abnormalities, 6 FLT3-ITD, 2 D835Mt, 4 MLL-PTD, 0 KIT, 2 NRAS and 2 KRAS mutations were found. FLT3-ITD and MLL-PTD were associated with a poor prognosis. Fifteen patients (9.5%) who had alterations of 2 of these 4 genes showed a poor prognosis. RAS gene mutations were found in 26 (16.5%) of 158 patients, but were not associated with the prognosis. These results suggest that a new different therapeutic strategy for the patients with these gene alterations in each subgroup, for example KIT mutations in t(8;21)-patients and MLL-PTD in patients with 11q23 translocation, is needed to improve the prognosis of pediatric AML.
Genomic Tumour Profiling with High-Density Oligonucleotide SNP Array in Sézary Syndrome.
Authors: Russo Giandomenico , Narducci Maria Grazia , Citterich Mauro Helmer , Picchio Maria Cristina , Critofoletti Cristina , Tocco Valeria , Scala Enrico , Sampogna Francesca , Frontani Marina , Arcelli Diego , Lombardo Giuseppe , Baliva Giannandrea , Caprini Elisabetta 
Published: October 2019

Abstract
Sézary Syndrome (SS) is a rare and aggressive form of Cutaneous T-Cell Lymphoma (CTCL) characterised by a distinct metastatic pattern mainly involving blood and skin and whose etiology and molecular pathogenesis are still unclear. Conventional cytogenetics studies have shown that most SS patients have chromosome aberrations; however allelotyping studies and genome-wide surveys for chromosome imbalances in this tumour are still very limited (Mao X. et al. 2003 Genes Chromosome Cancer 36:250–260). High-density single nucleotide polymorphism (SNP) arrays allow high-resolution and genome-wide detection of both loss of heterozygosity (LOH) and copy number (CN) abnormality. Therefore we used Affymetrix 10K SNP mapping array containing 11,560 tiled SNPs to investigate genomic aberrations of 13 individuals affected by SS. Genotype calls and signal information were obtained using GeneChip Operating Software (GCOS 1.4) and GeneChip DNA Analysis Software (GTYPE4.0). SNP calls were exported to be analysed with DNA-chip Analyser (dChip v1.3+) genotyping software which allows the simultaneous measurement of DNA copy number changes and LOH events (Zhao X. et al. 2004 Cancer Res. 64:3060–71; Lin M et al. 2004 Bioinformatics 20:1233–40).
Our findings indicate that chromosomes 17p, 10/10q and 9 are most frequently affected by LOH events, while gains of CN were observed more often for chromosome 17q and 8/8q. Among our patients almost all individuals showing loss of the 17p arm have also gain of the 17q, suggesting the presence of the isochromosome 17q, a frequently reported abnormality in SS. In addition to this, we characterised the chromosome LOH pattern identifying seven regions of significant loss shared by multiple tumours. Sample clustering based on significant LOH regions identified two groups of patients: one of them consists of 4 patients with a lower rate of chromosomal losses while the other contains 9 patients mainly characterised by the co-occurrence of LOH at chromosome 17 and chromosome 10.
The frequency and pattern of chromosomal changes in our group of 13 SS patients are in substantial agreement with previously described results using more conventional techniques, demonstrating the feasibility of the 10K SNP mapping array system to assess allelic imbalance in this tumour. The genome-wide approach and SNP high density allowed the identification of a larger number of LOH regions, including, however, those already described (chromosome 9p, 10q and 17p). Even though no significant statistical association can be observed due to the low number of cases available, we observed a lower overall survival in the group of 9 patients showing simultaneous LOH events at chromosome 17 and 10.
Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) Monitoring of Minimal Residual Disease (MRD) in Core Binding Factor Acute Myeloid Leukaemia (CBF AML).
Authors: Lane Steven W. , Saal Russell , Mollee Peter , Grigg Andrew , Taylor Kerry , Seymour John Francis , Kennedy Glen , Williams Bronwyn , Jones Mark , Grimmett Karen , Griffiths Vanessa , Gill Devinder , Hourigan Matthew , Marlton Paula 
Published: October 2019

Abstract
Background: CBF AML, with t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) and the associated fusion proteins AML1/ETO or CBFβ/MYH11, has a favourable clinical prognosis although significant numbers of patients still relapse. We examined the prognostic utility of MRD monitoring by RQ-PCR and propose a simple model for prediction of impending haematological relapse.
Methods: Patients with CBF AML had samples collected at diagnosis, after induction and consolidation chemotherapy and at routine regular intervals thereafter. RQ-PCR, using the Applied Biosystems 7700 Sequence Detection System, was performed in triplicate and the final result was calculated by averaging 3 values, expressed relative to PGK levels. Stratified Cox regression was used to assess the impact of predictor variables (diagnostic, post-induction, post-consolidation RQ-PCR levels and presence of a 1 log10 increase in sequential RQ-PCR levels) on leukaemia-free survival (LFS).
Results: Of 46 patients identified with CBF AML, 29 had diagnostic, regular longitudinal samples and clinical follow up allowing further evaluation; 12 AML1-ETO and 17 CBFβ-MYH11. The median age was 39 years (range 7–68) with 52% male. Median follow up was 34 months (range 1–106) and median sample number was 6 (2–15). Twelve relapses occurred at a median of 11 months (range 4–17) from diagnosis. There were significant differences between transcript levels at diagnosis (median 1.9), post-induction (8.96*10−04), post-consolidation (5.01*10−05), in remission (1*10−06) or relapse (0.15) (p=0.01). Diagnostic, post-induction and post-consolidation RQ-PCR levels did not predict outcome. A log10 rise in a remission bone marrow sample correlated with adverse LFS and imminent risk of haematological relapse (HR 8.6). Relapses occurred a median of 60 days (range 45–272) after a log10 rise.
RQ-PCR levels Hazard Ratio (HR) LFS 95% CI P-value Diagnosis 0.22 0.02–2.9 0.25 Post-induction 1.3 0.8–2.1 0.36 Post-consolidation 0.8 0.5–1.2 0.27 1 log10 increase 8.6 1.8–42 0.008
Conclusions: A 1 log10 rise in transcript levels was a highly significant predictor of haematological relapse. Transcript levels at early post-treatment time points did not predict long term outcome, cautioning against de-escalation protocols based on these results. Prospective identification of high risk patients will enable clinical trials to address the efficacy of treatment initiated at molecular progression.