bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional Activation of the Cardiac Homeobox Gene CSX1/NKX2-5 in a B-Cell Chronic Lymphoproliferative Disorder.
Authors: Su Xinying , Busson Maryvonne , Delabesse Eric , Azgui Zahia , Berger Roland , Merle-Beral Hélène , Bernard Olivier A. , Nguyen-Khac Florence 
Published: April 2020

Abstract
Transcription deregulation resulting from genomic rearrangement is frequently observed in human lymphoid malignancies. For example, chromosomal aberrations, such as translocations or inversions, involving the immunoglobulin (Ig), T cell receptor (TCR) and the BCL11B loci, are expected to juxtapose the strong regulatory elements of these genes to the affected genes on the other chromosomes, resulting in such activation. Recently, ectopic activation of two orphan homeobox genes located ~2Mb apart on chromosome 5q35, HOX11L2/TLX3 and CSX1/NKX2-5 have been described, as a result of their fusion to BCL11B on chromosome 14q32 in acute lymphoblastic leukemia of T-lineage. Fusion of TLX3 to TCRδ has also been reported. We describe a novel translocation t(5;14)(q35;q11) identified in a case of B-cell chronic lymphoproliferative disorder. FISH and molecular studies located the chromosome 14 breakpoint within the TCRδgene, at the Dδ3 segment, and the chromosome 5 breakpoint 2.5kb downstream (telomeric) of the NKX2-5 gene. As a result of this translocation, both NKX2-5 and TLX3 were transcribed, whereas only NKX2-5 was detected at the protein level. To investigate the expression of these two genes in B-cell chronic proliferations, we screened 20 B-cell chronic lymphocytic leukemias (B-CLL) and 21 atypical B-CLL samples by RT-PCR and RQ-PCR. No sample demonstrated NKX2-5 expression and only one patient showed TLX3 expression. This patient had an evolutive B-CLL, with complex chromosomal abnormalities, without involvement of the band 5q35. In conclusion, this study identifies a new translocation involving a NK-like homeobox gene in a mature B lymphoproliferative disorder, underscoring precedent identification of NKX2-5 activation in two human lymphoid leukemia cell lines. It also demonstrates that deregulation of homeobox encoding genes is not a specific feature of acute leukemic proliferations, but is also observed in chronic malignancies.
Lymphoma Associated Chromosomal Abnormalities Can Be Easily Detected by FISH on Tissue Imprints. an Underused Diagnostic Alternative.
Authors: Buño Ismael , Nava Paola , Alvarez-Doval Angela , Simon Ainhoa , Gema Gonzalez-Pardo , Alvarez-Rodriguez Federico , Diez-Martin Jose L. , Menarguez Javier 
Published: April 2020

Abstract
Detection of specific chromosomal abnormalities is essential in the diagnosis of several lympholiferative disorders. However, conventional cytogenetic studies are not frequently carried out from biopsies as it is in bone marrow (BM) specimens. On the contrary, FISH is usually performed on paraffin embedded tissue, an alternative with potential technical nuances both in its application and its interpretation. In our experience, FISH on tissue imprints is the ideal alternative to overcome these problems. In the present study, 46 tissue imprints and 17 BM smears from 43 patients with lymphomas were selected to investigate the presence of t(14;18)(q32;q21), t(11;14)(q13;q32), t(8;14)(q24;q32) and t(3;var)(q27;var). Representativity of the samples was assured prior to FISH by rapid May-Grümwald staining (Diff-Quick, QCA, Spain). Twenty imprints from reactive palatine tonsils and adenoids were used as negative controls. FISH was performed with specific dual-color dual-fusion FISH (D-FISH) probes for the first 3 translocations and a dual-color break-apart FISH probe for t(3;var)(q27;var) following the instructions of the probes supplier (Vysis, Inc). All except one sample (a BM smear stored at room temperature over 9 years), rendered satisfactory FISH hybridizations. In any case, all 43 patients could be successfully studied by FISH (the case referred above in which FISH failed in a first attempt was successfully analyzed using a different sample). The results supported the suspected diagnosis of follicular lymphoma in 22 patients, mantle cell lymphoma in 12 patients, large B-cell lymphoma in 5 patients, marginal zone lymphoma in 2 patients and B chronic lymphocytic leukemia in 2 patients. In one case, the observation of t(11;14) by FISH allowed to reclassify the case from follicular to mantle cell lymphoma and also to demonstrate clonal evolution by studying sequential tissue imprints stored for more than 6 years. Negative results also aided in the assignment of patients to proper diagnostic categories. FISH performed on tissue imprints and BM smears constitutes an optimal strategy for retrospective and prospective investigation of chromosomal abnormalities in lymphomas. Tissue imprints and BM smears conventionally stored at room temperature even for long periods of time can be safely used and sent by ordinary mail without special considerations for this purpose. Based on our experience we recommend to perform and routinely store tissue imprints whenever fresh tissue is available.
Heterogeneous Chromosomal Mechanisms Generating the 5′RUNX1/3′CBFA2T1 Gene in Acute Myeloid Leukemia.
Authors: Specchia Giorgina , Albano Francesco , Anelli Luisa , Zagaria Antonella , Liso Arcangelo , La Starza Roberta , Mancini Marco , Cuneo Antonio , Saglio Giuseppe , Fazi Paola , Testoni Nicoletta , Vicari Laura , Liso Vincenzo , Rocchi Mariano 
Published: April 2020

Abstract
Translocation t(8;21)(q22;q22) is a common karyotypic abnormality detected in about 15% of Acute Myeloid Leukemia (AML) cases. The rearrangement results in fusion of the RUNX1 (also known as AML1) and CBFA2T1 (also known as ETO) genes generating a 5′RUNX1/3′CBFA2T1 transcriptionally active fusion gene on derivative chromosome 8. In 1 to 8.5% of AML cases insertions events generating a 5′RUNX1/3′CBFA2T1 fusion gene have been reported, whereas the occurrence of inversions accompanying the t(8;21) has never been observed. We report a screening of 82 AML cases bearing the RUNX1/CBFA2T1 rearrangement detected by RT-PCR; all cases were tested by Fluorescence In Situ Hybridization (FISH) with BAC and PAC clones specific for CBFA2T1 and RUNX1 genes. This analysis allowed us to reveal five cases with ins(21;8), one with ins(8;21), and two with a pericentric chromosome 8 inversion followed by a t(8;21) translocation. A detailed molecular cytogenetic characterization of breakpoints has been performed in all cases.
FISH co-hybridization experiments with CBFA2T1 and RUNX1 probes revealed the presence of a functional fusion gene on the der(21) instead of the der(8) chromosome in five cases with ins(21;8); a single fusion signal on the der(8) chromosome was detected in the case with ins(8;21). The use of the same clones in FISH studies showed the presence of a single unexpected fusion signal on the 8p derivative chromosome in addition to faint CBFA2T1 and RUNX1 signals on the long arm of der(8) and der(21) chromosomes, respectively. These results suggested that a pericentric chromosome 8 inversion involving CBFA2T1 gene occurred and that the chromosome 21 was rearranged with the 8p derivative chromosome.
Appropriate chromosome 21 and 8 BAC clones were employed to precisely define the size of inserted regions in cases with insertions and the breakpoint on the 8p derivative chromosome in cases showing pericentric chromosome 8 inversion. The insertion size turned out to be very heterogeneous, ranging from a minimum of 2.4 Mb to a maximum of 44 Mb. In both cases with chromosome 8 inversion, the CBFA2T1 gene represents the breakpoint at the chromosome 8 long arm whereas the 8p breakpoint showed different mapping positions in 8p21.3 and 8p21.1, respectively.
Our results illustrate that (1) heterogeneous mechanisms can lead to the generation of the 5′RUNX1/3′CBFA2T1 chimeric gene; (2) molecular cytogenetic techniques may identify cryptic chromosomal changes, not detected by conventional cytogenetic analysis; (3) the crucial role of the 5′RUNX1/3′CBFA2T1 fusion gene in leukemogenesis does not depend on its location.
Discovery and Characterization of a Novel Large Non-Coding RNA Transcript, the Mouse Alpha Gene.
Authors: Lin Rui , Liu Cheng , Edgington Thomas S. 
Published: April 2020

Abstract
Recently, a new class of RNAs has been identified that, like mRNAs, are usually transcribed by RNA polymerase II, but lack significant translated open reading frames. They are non-coding RNAs (ncRNAs) that exert roles directly as RNAs, and function as genetic regulators, or riboregulators. In the present study, we discovered a novel very large ncRNA. From differential gene profiling of CD31 positive tumor microvascular endothelial cells from a murine colon carcinoma, we amplified an ~380 bp nucleotide sequence, DP100. This RNA was present in tumor cells as well as tumor vascular endothelium. The full-length DP100 transcript is an ~7 Kb RNA lacking an open reading frame set for more than 66 amino acids. Also the hypothetically predicted proteins lacked significant similarity to known proteins, consistent with identity of DP100 as an unusually large non-coding RNA transcript. Further bioinformatic search demonstrated that the full-length DP100 sequence is highly homologous to the human alpha gene, which encodes an 8.5 Kb, non-coding RNA transcript, and is located in a region implicated in chromosomal abnormalities of human tumors. The full-length DP100, here designated the mouse alpha gene, is evolutionally highly conserved among vertebrates, suggesting its functional significance. The role for this ncRNA in cellular behavior is under investigation.
PML/RARα Mediates Resistance to Apoptosis and Down-Regulation of the NF-κB Pathway in Acute Promyelocytic Leukemia.
Authors: Garcia-Casado Zaida , Cervera Jose , Pajuelo Juan C. , Valencia Ana , Garcia Carlos , Martin Guillermo , Bolufer Pascual , Barragan Eva , Ballester Sandra , Oltra Juan S. , Martinez Nerea , Marty Maria L. , Piris Miguel A. , Sanz Miguel A. 
Published: April 2020

Abstract
Acute promyelocytic leukemia (APL) is genetically characterized by the translocation t(15;17) that results in the fusion gene PML/RARα. The chimeric protein renders hematopoietic progenitor cells resistant to FAS-, TNF- and IFN-induced apoptosis and caspase-3 activation, supporting a role for apoptosis impairment in the pathogenesis of APL. To better investigate apoptosis deregulation in APL, we analyzed the expression profile of 53 newly diagnosed APL patients (27M/26F; median age: 41 yr. (range: 9–80); median WBC count x 109/L: 2.67 (range: 0.5–128); median platelet count x 109/L: 19 (range: 4.4–135); FAB subtype: 39 M3/14 M3v) using the OncoChip®, a cDNA microarray especially designed for analyzing genes involved in cancer which contains 6,386 genes. After array processing, a total of 371 and 249 known genes were found to be ≥2 fold down- or up-regulated, respectively. To verify the results of microarray analysis, six differentially expressed genes (JAG1, JUN, CDKN1C, FAS, TRAIL, TRAF6 and MMP9) were tested by real-time quantitative PCR analysis (Q-RT-PCR). As initially hypothesized, numerous genes involved in apoptotic pathways were deregulated. In particular, we found a significant down-regulation of genes involved in the activation of NF-κB and of genes related to TNF-mediated apoptosis (FAS, TRAIL, TNFSF13B), with 46 and 24 genes deregulated, respectively. Expression changes in other genes implicated in apoptosis were also identified, being of special interest those affecting to the BCL2 family. Thus, anti-apoptotic genes BCL2 and BCL11A were up-regulated while pro-apoptotic members of the family were down-regulated in the analyzed series. Genes involved in the regulation of p53-dependent apoptosis (such as APAF1, p53DINP1, ATM), as well as numerous genes involved in diverse mechanisms of DNA repair, were also inhibited. Finally, the protein kinase C-δ (PKCδ) and several interferon- and interleukin-related genes were also infraexpressed in APL. These findings suggest that inactivation of apoptotic pathways is a common event in the pathogenesis of APL and may have important implications in the design of therapeutic protocols. It was of particular interest the unexpected inhibition of the NF-κB pathway. It could be in accordance with the hypothesis that NF-κB is an inductor of apoptosis under some circumstances. The role of NF-κB in promoting or repressing cell death in APL should be further investigated.
Serial Analysis of Gene Expression Revealed Consistent Downregulation of More Than 100 Genes in Hodgkin Lymphoma.
Authors: Kluiver Joost , Schwering Ines , de Jong Debora , Küppers Ralf , Poppema Sibrand , van den Berg Anke 
Published: April 2020

Abstract
Hodgkin Lymphoma (HL) is unique in its cellular composition, consisting of a minority of tumor cells in an inflammatory background. The tumor cells (Reed-Sternberg cells, RS cells) are thought to be derived from germinal center B cells (centroblasts, CB) that have escaped apoptosis during antigen selection. Global gene expression studies in HL have been hampered by the fact that RS cells only represent less than 1% of the cells in the tumor tissue. Only a few large-scale gene expression studies are available, mostly using cell lines derived from patients with classical HL. To get more insight into the gene expression profile of RS cells we applied the Serial Analysis of Gene Expression Technique (SAGE) on several HL cell lines. SAGE was performed on the cell lines L428 and L1236 (classical cell lines, cHL), DEV (Nodular Lymphocyte Predominant cell line, NLP) and on CB as normal counterparts.
In total, about 100.000 tags were sequenced (Table 1). After normalization and exclusion of tags present only once, 3.635 genes were retained and used for further analyses. A five-fold difference in tag frequency between the HL cell lines and CB was used to select for up- or downregulated genes. Although many genes were upregulated in every individual HL cell line compared to CB, only few genes were consistently upregulated. In contrast, comparison of the downregulated genes revealed that 125 were downregulated in all three HL cell lines compared to CB (Table 2). Tags corresponding to Fascin, TARC/CCL17 and BIC, known to be highly expressed in HL indeed were observed in the SAGE libraries. Among the genes downregulated in L428 a loss of B lineage-specific genes was observed confirming the previous findings in L1236. Interestingly our SAGE results suggest that the NLP cell line DEV has an intermediate loss of B-lineage specific genes compared to CB. To gain more insight in the biology, differentially expressed genes were grouped according to gene ontology’s (based on biological process or molecular function) and pathways. We have now selected more than 70 genes that will be subjected to quantitative RT-PCR analysis to confirm our SAGE results and to study their expression in tumor cell enriched HL samples.
In conclusion: Downregulation of gene expression seems to be important in the pathogenesis of HL since we observed a consistent downregulation of more than 100 genes in HL compared to CB.
Table 1. Overview of Hodgkin lymphoma SAGE libraries
Table 2. Number of up- and downregulated genes in Hodgkin lymphoma compared to centroblasts
Library DEV L428 L1236 CB HL type NLP cHL cHL Centroblasts Tags 16316 20990 30623 29787 Genes 4703 5602 10561 11095 L428 L1236 cHL DEV cHL & NLP HL L428 and L1236 are derived from classical Hodgkin lyphoma (cHL) cases, DEV is derived from a case of Nodular Predominant Hodgkin lymhoma (NLP HL) Upregulated 396 116 14 330 7 Downregulated 329 169 141 309 125
Hypermethylation of the p15/INK4B Gene in Fanconi Anemia.
Authors: Hamanoue Satoshi , Yabe Miharu , Yabe Hiromasa , Yamashita Takayuki 
Published: April 2020

Abstract
Fanconi anemia (FA) is an inherited bone marrow failure syndrome with multiple complementation groups, characterized by genomic instability and predisposition to MDS and AML. Recent evidence indicates that multiple FA proteins are involved in DNA repair. Thus, increased genetic damage and secondary dysregulation of cell proliferation, differentiation and apoptosis are thought to play important roles in the development of bone marrow failure and subsequent progression to MDS/AML. However, little is known about molecular abnormalities responsible for these hematological disorders. Numerous studies indicated that epigenetic silencing of p15/INK4B, an inhibitor of cyclin-dependent kinases, plays an important role in the pathogenesis of MDS and AML. In the present study, we examined methylation status of 5′ CpG islands of the p15 gene in bone marrow mononuclear cells of FA patients, using methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Bone marrow samples were analyzed in 10 patients and serially studied in 4 of them. Hypermethylation of the p15 promoter region was detected in 5 patients (50%). This group included 3 patients with MDS: FA28-1 with refractory anemia (RA), FA87 with RAEB (RA with excess of blasts), and FA88 with later development of RA and progression to RAEB; whereas myelodysplasia was not observed in 2 patients (FA89, FA90). In two cases (FA88, FA90), p15 hypermethylation became negative during their courses, perhaps because of decreased myeloid cells. On the other hand, none of 5 patients without p15 hypermethylation had MDS. These results suggest that p15 hypermethylation is associated with development of MDS and occurs in the early phase of clonal evolution in the disease. Methylation status of p15 may be a useful prognostic factor of FA.
Patient Age at onset (year old) Time from onset (month) Cytopenia MDS Cytogenetic abnormalities p15 methylation MSP b p15 methylation COBRA c a siblings, b MSP: methylation specific PCR, c COBRA: combined bisulfite restriction analysis, d ND: not determined FA28-1a 5 128 severe RA − − + 133 severe RA − + ++ FA87 8 252 severe RAEB + + +++ FA88 5 31 moderate − − + +++ 45 severe RA + − − 58 severe RAEB + + + FA89 5 49 mild − − + + 56 severe − − + + FA90 2 2 mild − − + ++ 31 severe − − − − FA28-2a 5 51 mild − − − NDd FA28-3a 3 12 mild − − − NDd FA47 3 15 mild − − − NDd FA68 5 46 moderate − − − NDd FA91 5 129 mild − − − NDd
Regulation of the GATA3 Promoter by Human T-Cell Lymphotropic Virus Type I Tax Protein.
Authors: Gilli Simone C.O. , Salles Tereza S.I. , Saad Sara 
Published: April 2020

Abstract
The HTLV-I nonstructural protein Tax plays a crucial role in cellular transformation. It activates the transcription factors of various cellular genes and interacts with cellular proteins. There is limited data available on the interaction between specific T cell transcription factor GATA3 and Tax. Implications for the significance of GATA3 in T-cell development and function, (Th2) differentiation, and a role of GATA3 during the immune response have been reported. We had previously demonstrated decreased GATA3 mRNA expression in HTLVI infected individuals and in patients with ATLL and HAM/TSP [Gilli et al., 2000]. To determine the effect of the Tax protein on GATA3 gene expression, we investigated the interaction between this protein and its promoter and repressor regions by DNA-protein interaction and “in vitro” transcription assays. Results demonstrated an interaction between Tax and the GATA3 promoter via the transcription factor Sp1 and a role for Tax in the negative regulation of GATA3 expression, through its interaction with the repressor ZEB. This interaction may be involved in the pathophysiology of adult T cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy.
Frequency of Genetic Deletions of the Glutathione-S Transferase (Gst) Gene in Mexican Patients with De Novo Acute Leukemia: A Preliminary Report from the “Instituto Tecnologico De Monterrey-Hematology Research Group”.
Authors: Escoboza Jose R. Borbolla , Garza-Madrid Marcos E. , Alvarado Martha , Baez Enrique , Lopez-Hernández Manuel A. , DeDiego Jose E. , Baltazar Severiano , Leon-Castanon Maria I. , Rojas-Martinez Julio C. , Ramirez-Assad Cecilia , Trueba Elvira , Villarreal Gerardo , Villela Luis M. , Cruz-Rico Jorge , Tejeda Monica , Duque Jorge , Gonzalez-Avante Mauricio C. , Pompa Teresa , Anaya Irene , Ochoa Leonel , Gonzalez Guadalupe , de la Luz Mendizabal Maria , Jimenez Rosa M. , Hernandez Roberto , Mejia Dolores , Romero Eduardo , Gil-Rondero Carlos , Juarez Jorge L. , De Leon Rosa E. , Tovar Yara E. , Penniecook Jason A. 
Published: April 2020

Abstract
Although there have been extraordinary advances in leukemia therapy, there is still a large subset of cases in which complete remission or prolonged leukemia-free survival cannot be achieved. Some of this variability in results is thought to be related to the differences in the effect of chemotherapy drugs on different patients. In many cases, these differences may be associated with the presence of genetic alterations that produce defective drug-metabolizing enzymes, drug transporters or drug targets. One of these is the glutathione-S transferase (GST) gene, which is known to catalyze the conjugation of toxic compounds, such as aliphatic aromatic heterocyclic radicals and epoxides, among others, to glutathione. The enzymes encoded by this gene detoxify polycyclic aromatic hydrocarbons and conjugated isothiocyanates.
Objective : Our aim is to evaluate the frequency of deletions in GSTT1 and GSTM1 of the GST gene in Mexican patients with de novo acute leukemia.
Methods : Starting in July 2003 and up until now, have included 75 samples from as many patients diagnosed with de novo acute leukemia, regardless of age, sex, or leukemia type. After obtaining informed consent, we drew blood, purified DNA and performed PCR to look for deletions in the GST gene (variants GSTT1 and GSTM1).
Results: We found GSTM1 positiveness in 54 samples (72%), of those, 24 (44.5%) were ALL and 30 (55.5%) AML. We had 18 samples (24%) positive for the GSTT1 deletion; of those, 10 (55.5%) were from patients with ALL and 8 (44.4%) from AML patients.
Conclusions ; As far as we can tell this is the first report of the frequency of these genetic deletions in Mexican acute leukemia patients. Recently a Mexican group studying the possible association of GSTT1 to lung cancer found that among Mexican controls, the frequency of this deletion was around 4.5%. This result would appear to indicate, as has been done by some other authors, that regardless of the possibility of becoming a prognostic factor, at least some polymorphism of the GST gene could be related to the genesis of this disease.