bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Distance Cyclin D1 Activation in B Cell Malignancies: Role of RNA Polymerase II.
Authors: Liu Hui , Wang Jin , Maziarz Richard T. , Epner Elliot M. 
Published: April 2020

Abstract
Translocations involving the immunoglobulin heavy chain gene locus (IgH) are common in B cell malignancies. One common target gene is cyclin D1, which is deregulated in most patients with mantle cell lymphoma (MCL) and approximately 15–20% of patients with multiple myeloma (MM). Cyclin D1 is not expressed in normal lymphocytes; cyclin D1 expression in B cell malignancies is deregulated by IgH translocations and insertions. We have shown that the cyclin D1 locus, including the promoter and upstream regions, are acetylated and DNA hypomethylated in both malignant and nonmalignant B cells (Liu et al, Blood in press). Using chromatin immunoprecipitation (ChIP) assays, we have found that RNA polymerase II (Pol II) is a) present at the cyclin D1 promoter b) located at regions far upstream of the cyclin D1 gene and c) present at 3′ Cα IgH regulatory elements only in cyclin D1 expressing malignant B cells. Pol II is present at the translocation breakpoint in a MCL cell line, but we do not find Pol II present continuously from the IgH regulatory regions to the cyclin D1 promoter. Confirmatory RT-PCR analyses also do not demonstrate continous evidence of RNA transcripts extending from the IgH regulatory elements to the cyclin D1 promoter. Mutants derived from gene targeting experiments that have lost the translocated chromosome show Pol II binding only at the Eu intronic enhancer, consistent with known promoter acivity and sterile transcripts originating at this location. Our data suggest that Pol II may play a important role in initiating long distance cyclin D1 deregulation by translocated IgH sequences. Analogous to the mouse β-globin gene locus, a polymerase transfer (LPT) model may be invoked, where other proteins such as CTCF effect Pol II transfer from 3′ Cα IgH regulatory sequences to the cyclin D1 promoter and initiate cyclin D1 transcription.
Constitutive FLT3 Activation Results in Specific Changes in Gene Expression in Myeloid Leukemic Cells.
Authors: Kim Kyu-Tae , Baird Kristin , Davis Sean , Levis Mark , Piloto Obdulio , Li Li , Chen Peili , Meltzer Paul , Small Donald 
Published: April 2020

Abstract
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 play an important role in leukemogenesis. They are the most common genetic alteration in AML and their presence is associated with poor prognosis. To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild type FLT3 signaling by cDNA microarray analysis. In order to minimize gene expression changes that might be drug specific and not related to FLT3 inhibition or might be cell-type specific, we used three different FLT3 inhibitors, CEP-701, CEP-5214, and AG1296, and three different constitutively activated FLT3-expressing leukemia-derived cell lines, EOL-1, MOLM-14 and MV4-11. We considered to be FLT3 responsive only those genes whose expression consistently changed in response to FLT3 inhibition by each of the three FLT3 inhibitors in all of the cell lines. RNA for hybridization to the microarrays was harvested from cells both before and after increasing times of FLT3 inhibition to determine genes which decreased or increased in response to FLT3 signaling. In addition, because the inhibitors are all reversible, RNA was also harvested from the cells at increasing times after release from FLT3 inhibition. This enabled us to confirm that, for example, genes whose expression appeared FLT3 dependent and were thus down-regulated by FLT3 inhibition, returned towards normal levels after FLT3 signaling was allowed to resume. Statistical analysis of the microarray results indicated a limited set of genes are highly and consistently affected by FLT3 inhibition and return toward pretreatment levels after release from inhibitor. We confirmed the cDNA microarray data using quantitative real-time PCR. Several of the most significantly affected genes are involved in the Ras/MAPK pathway including DUSP6, DUSP7, MAPK6, TNF, and cMyc. Other sets of genes are involved in JAK/STAT or Wnt signaling pathways including Pim-1, cMyc, Cyclin D3, IL4 receptor, and CISH. These genes are all consistently down-regulated after FLT3 inhibition. These data further confirm the role of constitutively activating FLT3 in mediating multiple signal transduction pathways. We also found several transcriptional factors (RUNX1/AML1, MAFG, XBP1, TGFBI4, and BRD8), several genes involved in receptor-mediated signaling (IL1RAP, CDC42EP3, PLAUR, LY64), and several genes involved in cell proliferation, metabolism, or structure (BCL7A, APTX, GHRH, SET7, ATAD2, CLIC1, CRIP2, MRPL12, VIM) to be consistently differentially expressed. In summary, we have found by cDNA microarray analysis and confirmed by QPCR, a consistent pattern of FLT3 dependent gene expression. The alteration of the gene expression profile in these cells is likely the mechanism of FLT3-mediated leukemogenisis.
Gene Expression Profiling Analysis in Splenic Marginal Zone Lymphoma Allows To Predict Survival and Histological Transformation.
Authors: Thieblemont C. , Ballester B. , Nasser V. , Gazzo S. , Doucet G. , Felman P. , Callet-Bauchu E. , Berger F. , Loi L. , Salles G. , Birnbaum D. , Coiffier B. , Houlgatte R. 
Published: April 2020

Abstract
Splenic Marginal Zone Lymphoma (MZL) is described as an indolent lymphoma with a long term survival. However classical prognostic factors can not distinguish between patients who are likely to have good or poor outcomes. Moreover histological progression occurs in 10–20% of cases at the time of recurrence, but may be present at diagnosis, inducing a shorter survival with a median around 2 years. New model based on molecular understanding are needed to better discriminate these patients for their prognosis and disease evolution.
Biopsy samples of splenic MZL from 43 patients treated in one institution and 8 with transformed splenic MZL were examined for gene expression using a nylon cDNA microarray consisting of 7, 000 human genes. Two of them came from a group of matched pair of splenic MZL and the transformed counterpart. An additional group comprising 4 transformed follicular lymphomas and 1 transformed small lymphocytic lymphoma were also analysed. Hierarchical clustering realized with all samples allowed to visualized patterns of gene expression already described in our previous work1 and corresponding to precise functions (proliferation, early response...), cell or tissue subtype (T cells, stroma …) or lymphoma subtype (MZL, MCL, SLL). The ability of individual genes to distinguish 1/ MZL and transformed-MZL subtypes, and 2/ alive patients and dead patients was calculated using a supervised method (discriminating score and bootstrap resampling). This allowed us to construct molecular predictors of survival and histological transformation.
Transformation discriminating genes regrouped 73 genes related to cell proliferation such as CDC10, CDK4, PRKDC, PLCG2, LDHA, MCL2, and NPM1. P53 was down-expressed in all the transformed samples. Survival discriminating genes regrouped 26 genes from a unique cluster related to cell proliferation such as LDHA, NME1, MYC, ENO1. Although these genes seem to participate to the same function, only one gene was found discriminating the 2 parameters (LDHA). Gene ontology analysis using GOminer showed that the histological transformation was more related to cyclin-dependent protein kinase and that the survival was more related to metabolism. We used 26 genes to construct a predictor for survival in MZL patients. This gene-based predictor allowed predicting survival (p &lt;0.00001) in MZL patients better than with classical prognostic factors (age, performance status, stage, LDH, monoclonal component, IPI…), but also in transformed MZL patients. In conclusion, genes involved in histological transformation and survival in MZL patients are implicated in independent but complementary functions leading to cell proliferation.
Hypermethylation of Retinoic Acid Receptor Alpha 2 (RARα2) Promoter in Human AML Cells Correlates with Poor RARα2 Expression and Response to Differentiation Inducers.
Authors: Glasow Annegret , von Lindern Marieke , Waxman Samuel , Arthur Zelent 
Published: April 2020

Abstract
All-trans retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation in non-APL AML cells. Treatment of ATRA non-responsive cells with the demethylating agent 5-Aza-2′-deoxycytidine (decitabine) restores RARα2 expression and differentiation response to ATRA in different AML subtypes, suggesting abnormal epigenetic changes as a possible mechanism underlying silencing of RARα2 and contributing to a differentiation deficit in these cells. Here we compared the methylation status of ATRA-inducible RARα2 and constitutive RARα1 promoters in 5 human AML cell lines and in normal human CD11b+/CD33+ leukocytes (NLs) by sequencing their respective bisulfite modified CpG islands. Whereas the CpG-island of the RARα2 promoter was completely methylated in all AML samples, it was not methylated in NLs nor in a control preB cell line, NALM-6. The methylation status of the RARα2 promoter directly correlates with the RARα2 expression level, which was shown by real-time RT-PCR to be 100–1000 fold higher in NLs or NALM-6 cells than in AML cell lines. Expression of RARα2 in human primary AML cells was found to be as low as in AML cell lines. In contrast, RARα1 promoter was not methylated in any of the samples and RARα1 expression levels were similar in AML cells and NLs. We have previously shown that stimulation of AML cell differentiation by ATRA and G/GM-CSF (GFs) is associated with a 10 fold induction of RARα2 expression through direct effects on receptor activity. We now show that pre- or co-treatment with decitabine results in up to 100 fold further increase in RARα2 expression levels, rendering the RARα2 mRNA levels similar to these observed in NLs. This synergism in RARα2 induction is paralleled by marked enhancement of leukemic cell differentiation. These results highlight the potential therapeutic use of epigenetic modifiers like decitabine, which may relieve the repression of aberrantly silenced genes required for cellular maturation and amplify the effects of differentiation inducers like ATRA and GFs in AML.
HDAC2 Plays a Role in Protecting t(14;18) Lymphoma Cells from Apoptosis by Up-Regulation of Bcl-2.
Authors: Duan Hong , Heckman Caroline A. , Boxer Linda M. 
Published: April 2020

Abstract
Histone deacetylases (HDACs) usually cause repression of gene expression through deacetylation of histones H3 and H4. Inappropriate transcriptional repression by HDACs has been observed in some malignancies, and several HDAC inhibitors are in clinical trials to treat solid tumors and hematologic malignancies. While the transcriptional activation of genes by HDAC inhibitors has been consistently associated with increased histone acetylation, transcriptional repression by HDAC inhibitors is less well understood. Previously, we showed that two structurally unrelated HDAC inhibitors, Trichostatin A (TSA) and Sodium Butyric Acid (NaB), induced apoptosis and down-regulated bcl-2 expression in follicular lymphoma cells, in which the t(14;18) translocation results in increased bcl-2 expression and resistance to apoptosis. In the current study we further explored the mechanisms underlying the HDAC inhibitor-induced bcl-2 transcriptional repression. Transient transfection of expression vectors encoding three Class I HDACs and real-time reverse transcriptase PCR analysis showed that while overexpression of HDAC2 consistently increased bcl-2 mRNA transcription, overexpression of HDAC1 and HDAC3 did not have a significant effect on bcl-2 levels. These results indicate that HDAC2 has a functional role in the regulation of bcl-2 expression. Furthermore, immunoprecipitation and Western blot analysis showed that TSA treatment dramatically increased the acetylation of two bcl-2 promoter sequence-specific transcription factors, Sp1 and C/EBPα, which are required for bcl-2 P1 and P2 promoter transcriptional activity as well as for TSA-induced bcl-2 transcriptional repression. Increased acetylation of Sp1 and C/EBPα was accompanied by decreased association of HDAC2 but not HDAC1 with these two transcription factors. More importantly, quantitative chromatin immunoprecipitation assays revealed decreased binding of HDAC2 but not HDAC1 to the bcl-2 promoter regions in vivo. These results suggest that posttranslational acetylation of Sp1 and C/EBPα by TSA disrupts the association of HDAC2 with them and leads to decreased binding to the bcl-2 promoters. The current study along with our previous findings suggest that HDAC2 may be an important target of HDAC inhibitor-induced bcl-2 transcriptional repression and provide a mechanistic rationale for the use of HDAC inhibitors in the treatment of human follicular lymphoma.
CA-125 as a Marker for the Early Diagnosis of Hepatic Veno-Occlusive Disease Following Hematopoietic Stem Cell Transplantation.
Authors: Zuckerman Tsila , Ben Harush Shani , Avivi Irit , Gavish Israel , Haddad Nuhad , Fineman Riva , Dann Eldad , Hoffman Ron , Brenner Benjamin , Rowe Jacob M. , Zuckerman Eli 
Published: April 2020

Abstract
Hepatic veno-occlusive disease (VOD), a common complication of hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity and mortality. The diagnosis is mainly based on clinical criteria that are neither sensitive nor specific enough to establish early diagnosis. CA-125 is a tumor marker, which may also increase in chronic liver disease, especially with ascites formation. Since VOD is known to result from liver injury and is associated with ascites, we examined whether CA-125 can be used as a serum marker for early diagnosis of VOD.
Methods: 74 consecutive patients undergoing HSCT were prospectively followed for clinical signs and symptoms of VOD. Serum samples for CA-125 were taken before conditioning, on day 0 and then every 7 days until patient’s discharge from hospital. CA-125 serum levels were measured by ELISA assay.
Results: 19 of 74 patients undergoing HSCT developed VOD according to Jones criteria. 89% of these patients underwent allogeneic stem cell transplantation, 47% received the regimen containing busulfan/cytoxan and 37% were treated with total body irradiation (TBI) and cytoxan. 26% of the patients had severe VOD. Diagnosis of VOD was established on average on day 7 (range 2–20). No difference in CA-125 was observed pre-transplant between the two groups (VOD versus non-VOD), but CA-125 levels increased in 68% of the patients with VOD as opposed to only 15% of those without VOD (p&lt;0.0001) on average on day 9 post transplant. In addition, the peak CA-125 levels were 149.2u/ml versus 45.6u/ml (p&lt;0.0001), respectively. On day 7 post transplant a cut off level of 43u/ml can detect VOD with specificity and sensitivity of 79% and 72%, respectively. The specificity rose to 94% in patients with normal CA-125 levels pre-transplant.
In conclusion: CA-125 levels rise early in patients developing VOD with a good sensitivity and specificity and can therefore be used as a marker in the diagnosis of VOD. Whether CA-125 is a true predictor for the development of VOD or is a surrogate marker needs to be evaluated prospectively by measuring day serum CA-125 levels starting on day 0. This is currently being evaluated in our center.
Prevention of Veno-Occlusive Disease in Hematopoietic Stem Cell Transplantation Due to Defibrotide Prophylaxis.
Authors: Hasenkamp Justin , Conradi Imme , Wulf Gerald , Jung Wolfram , Truemper Lorenz , Glass Bertram 
Published: April 2020

Abstract
Veno-occlusive disease (VOD) is a serious complication of intensive chemotherapy regimens used in hematopoietic stem cell transplantation (HSCT). Incidence ranges from 10–60% (Chopra et al., 2000). Despite numerous therapeutic attempts described such as rtPA, TIPS and defibrotide mortality remains 80% (Fried et al., 1996). Risk factors for developing VOD are previous high-dose chemotherapy, unrelated donor transplants and busulfan-based conditioning regimens. In face of the frequency and high mortality due to absence of effective therapeutic options there is need for prophylaxis. We incorporated defibrotide into the supportive regimen for high risk patients undergoing a HSCT with busulfan containing conditioning regimens. From 01/2003 to 08/2004 44 patients (median age 52y, 24 male) receiving a busulfan containing regimen for HSCT (2 autologous, 42 allogeneic, 23 unrelated donors) were treated prophylactically with defibrotide as 800mg/24h continuous infusion from start of conditioning chemotherapy up to day +21 (group 1). Underlying diseases were: 10 AML, 24 NHL, 3 HD, 6 MM, 1 CML. Median number of previous regimens were 3. 27 patients had high-dose chemotherapies followed by autologous HSCT as prior therapy. From 07/2001 to 12/2002 16 patients (median age 45y, 11 male) receiving busulfan-based conditioning for allogeneic HSCT (7 unrelated donors) received heparin (300IE/h) for prophylaxis of VOD and catheter related thrombosis (group 2). Disease entities were 7 AML, 7 NHL, 1 HD, 1 ALL. Median number of previous regimen was 3. 11 patients had high-dose therapies followed by autologous HSCT as prior therapy. While in the latter group 1/16 patients developed and finally died of VOD, 3/44 in the defibrotide group did so. Date of VOD diagnosis in the patient not prophylatically treated with defibrotide was day +13 after HSCT compared to day +21, +25 and +27 in patients who received defibrotide prophylaxis. There were no serious adverse events (e.g. bleeding) attributable to defibrotide. Overall incidence of VOD in both groups is low (6,8% group 1; 6,3% group 2). Although patients in group 1 were at high risk of VOD, no VOD occurred during the period of defibrotide prophylaxis. We conclude that defibrotide is save and efficient in prevention of VOD. Defibrotide delayed the onset of VOD beyond its application. However, with defibrotide prophylaxis late onset of VOD has to be encountered. The optimal application period has to be determined.
Venocclusive Disease of the Liver Is Associated with the Early Development of Post-Transplant Microangiopathy in Allogeneic Stem Cell Transplantation.
Authors: Zeigler Zella Rose , Shadduck Richard K. , Lister John 
Published: April 2020

Abstract
Thirty-three patients were followed prospectively for the development of venocclusive disease (VOD) of the liver and Post-Transplant Microangiopathy (PTM) on days 0,7,14,21,30,60,90 following allogeneic stem cell transplantation. The grading system of Zeigler, ZR et al (Bone Marrow Transplant, 1995) was used to categorize patients with the clinical syndrome of PTM. The diagnosis of venocclusive disease was made using the criteria of Jones, RJ, (Transplantation, 1987). Patients with and without VOD had similar peak grades of PTM, that ranged for Grade 2 – 4. However, the development of PTM occurred earlier in those with VOD. Data regarding the development of PTM is shown in the Table below as medians and 10th and 90th percentiles. Patients following allogeneic SCT without evidence of PTM have a median % fragmented cells of 1.4% (10th and 90th percentiles of 0.2 and 3.6%). Median LDH elevations expressed as x ULN in patients following allogeneic SCT (without evidence of PTM) were 0.5 ( 10th and 90th percentiles of 0.5–1.0).
When compared with patients without VOD, patients with VOD experienced earlier an earlier onset and a higher grade of PTM. The sequence of events is an increase in bilirubin assoicated with an elevation of the LDH level at day 7 followed by the recognition of grade 2 or higher PTM by day 14. There is also an increase in fragmented cells differentiating the two groups by day 21. By day 28, those patients with VOD who have survived have similar LDH and fragmented cell levels as those that did not have VOD. We conclude that PTM that occurs less than or equal to day 21 post-SCT represents regimen toxicity and often accompanies the diagnosis of VOD.
Parameter With VOD N=15 Without VOD N=18 P Day to Development of PTM 14 (7–31) 33 (21–58) &lt;0.001 Day to peak PTM 18 (14–32) 43 (7–112) 0.02 LDH x ULN Day 7 1.0 (0.5–2.1) 0.6 (0.5–0.8) 0.02 LDH x ULN Day 14 1.5 (0.7–3.7) 0.7 (0.5–2.5) &lt;0.01 LDH x ULN Day 21 2.3 (0.7–12.2) 0.9 (0.7–1.6) 0.01 % FC Day 21 6.7 (1.8–17) 2.0 (0.2–3.8) &lt;0.01 Bilirubin (mg/dl) Day 7 3.3 (1.2–6.5) 1.0 (0.5–2.7) &lt;0.001
Rasburicase Improves Renal Function and Uric Acid Nephropathy in Patients Developing Acute Renal Failure after Conditioning for Hematopoetic Stem Cell Transplant (HSCT).
Authors: Strader Donovan , Oholendt Michael S. , Popat Uday , Carrum George , Heslop Helen E. 
Published: April 2020

Abstract
Significant reduction in renal function secondary to protein deposition in the renal tubules is a common occurrence among patients with plasma cell dyscrasias such as Multiple Myeloma (MM) and Amyloidosis undergoing HSCT. Conditioning chemotherapy and uric acid release following cellular lysis may worsen already compromised renal function, leading to acute renal failure. Rasburicase, a recombinant urate oxidase enzyme, has been approved by the U.S. Food and Drug Administration for the treatment and prevention of hyperuricemia associated with tumor lysis syndrome in pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing chemotherapy. We hypothesized that prompt treatment of hyperuricemia with rasburicase may prevent uric acid nephropathy and improve renal function, obviating the need for dialysis and improving the eventual outcome. Six adults, four with MM and two with amyloidosis, with rising uric acid levels after high dose Melphalan (200mg/m2) were given a single dose of rasburicase (0.15 mg/kg). At baseline, all patients had rising serum creatinine [mean: 2.1 mg/dL (range: 0.9–4.5 mg/dL)], rising BUN [mean: 27.6 mg/dL (range: 1.3–70 mg/dL)], and declining creatinine clearance (CrCL) [mean: 50.5 ml/min (range: 16–75 ml/min)]. After one dose of rasburicase, renal function significantly improved according to CrCL at 48 hours [mean: 55.2 ml/min (range: 17–82 ml/min)] and continued to improve at five days [mean: 68.2 ml/min (range: 18–109 mg/dL)]. Baseline uric acid was elevated [mean: 8.61 mg/dL (range: 7–9.9 mg/dL)] and improved 24 hours after treatment with rasburicase [mean: 0.2 mg/dL (range: 0–0.6 mg/dL)]. None of the patients required renal replacement therapy. There were no serious adverse events associated with rasburicase therapy. We therefore conclude that a single dose of rasburicase is promising in improving deteriorating renal function post high dose chemotherapy in patients with compromised renal function; further controlled studies are warranted.