bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of Circulating Plasmacytoid Dendritic Cells in Chronic Myelogenous Leukemia and Their Restoration after Interferon-alpha or Imatinib Mesylate.
Authors: Rossignol Alexis , Barra Anne , Roy Lydia , Guilhot Francois , Turhan Ali G. , Gombert Jean-Marc 
Published: October 2019

Abstract
It is currently established that the immune system plays a critical role in the control of chronic myelogenous leukemia (CML). Several cell populations including T cells, dendritic cells (DC) and NK cells have been shown to exhibit potential anti-leukemic activities. The possible role of plasmacytoid dendritic cells (pDC) in this anti-leukemic response has not been explored so far. As pDC are the major source of interferon(IFN)-α in vivo, the frequency and the function of circulating pDC were compared in CML patients and in healthy subjects. Three groups of CML patients were studied:
chronic phase patients (CP) (i.e. at diagnosis or unresponsive to treatment); patients in complete/major cytogenetic remission induced by IFN-α and patients in complete/major cytogenetic remission induced by imatinib mesylate (IM).
Flow cytometric analysis of pDC (assessed by the strong co-expression of CD123 and CD303, formerly BDCA2) showed a dramatic depletion of pDC compartment in CP patients (n = 11) as compared to healthy donors (n = 9) (0.99 versus 5.71 pDC/μL of blood, respectively). Moreover, their functional capacity to produce IFN-α after peripheral blood mononuclear cells (PBMC) stimulation with influenza virus was abolished (883 versus 8201 pg/ml of supernatant, respectively). Patients treated with IFN-α exhibited a complete and long-termed restoration of pDC compartment (4.88 pDC/μL of blood) and of IFN-α production (6932 pg/ml), which was sustained even after the treatment was stopped. In contrast, although IM therapy led to the complete restoration of IFN-α production (6662 pg/ml), its effect on circulating pDC number remained solely partial (2.82 pDC/μL of blood). This last observation and the absence of any linear relationship between pDC number and IFN-α production in patients in complete remission suggested that treatments, and more particularly IM, were able to induce “pDC-independent” pathways of in vivo IFN-α production. Consistently with this hypothesis, we found that pDC-depleted PBMC from patients in cytogenetic remission were able to produce IFN-α, whereas those from healthy donors were not. As a conclusion, our results show for the first time that IFN-α and IM treatments reverse the quantitative and functional impairment of pDC compartment in CP CML patients. They also suggest that these treatments are able to induce differentiation mechanisms leading to the generation of new IFN-α producing cell populations.
MLL Modulates Telomere Length in Mammalian Cells.
Authors: Caslini Corrado , Hess Jay L. 
Published: October 2019

Abstract
In mammalian cells, the telomeric complex at the end of chromosomes consists of several thousand copies of the exanucleotide TTAGGG and associated proteins attached to the nuclear matrix. Chromatin modifying enzymes involved in histone H3/lysine 9 and histone H4/lysine 20 trimethylation, and DNA methylation are known to preserve the telomere heterochromatic structure, length and capping function. Loss of these heterochromatic marks leads to telomere lengthening, most likely through the negative regulation of telomerase or alternative lengthening of telomeres (ALT) mechanisms. The MLL protein is a chromatin modifying enzyme with histone H3/lysine 4 methyltransferase activity, which maintains active transcriptional state of target genes in a large multiprotein complex. Analogously, the yeast’s MLL homologous protein Set1 is part of a multiprotein complex required for maintenance of target genes expression. In addition, Set1 deletion mutants show disruption of telomeric silencing along with telomere shortening or lengthening, respectively in budding and fission yeast. This raised the question of whether MLL, like Set1, plays a role in epigenetic maintenance of telomeric heterochromatin. Here, using chromatin immunoprecipitation (ChIP) analysis, we show that MLL associates with the heterochromatic complex at telomeres of primary and transformed human cell lines. ChIP analysis of cell lines conditionally expressing Flag-tagged MLL chimeric proteins and deletion mutants shows the amino terminus of MLL, which confers association to the nuclear matrix, is responsible for targeting to the telomeric complex. MLL associates with the telomeres of telomerase and ALT positive cell lines in amount that is proportional to the telomere length, as revealed by Southern blot terminal restriction fragment analysis. Moreover, immunoprecipitation analysis evidenced the association of MLL with the terminal-repeat binding factor TRF2, a protein known to play a key role in telomere capping, and indirect immunofluorescence analysis showed MLL and TRF2 colocalization at ALT-associated PML nuclear bodies.
In search for possible biological functions of MLL at the telomeric complex, we found abnormally longer telomeres in Mll-null mouse embryonic stem (ES) cells and fibroblasts (MEFs) than in wild-type control cells. In Mll-null MEFs, a significant telomere shortening was obtained by stable reexpression of an MLL allele. In addition, we found that in aging human cells the MLL binding to the telomeric complex is abrogated by the progressive telomere shortening due to telomere attrition, suggesting a possible involvement of MLL in signaling for replicative senescence.
Acetylation of a Conserved Lysine Residue within Activation Domain One of E2A Transcription Factors Plays a Role in Transcriptional Regulation.
Authors: Hyndman Brandy D. , Bayly Richard , LeBrun David P. 
Published: October 2019

Abstract
The E2A locus encodes transcription factors, called E12 and E47, involved in lineage-specific cellular differentiation. The locus is also involved in chromosomal translocations associated with acute lymphoblastic leukemia, the most common of which results in expression of the oncoprotein E2A-PBX1. We showed recently that direct interaction between E2A and the histone acetyl-transferase (AT) and transcriptional co-activator proteins CBP/p300 is required in leukemogenesis by E2A-PBX1. E2A proteins have also been shown to interact with another AT/co-activator, p/CAF. Interaction with these AT proteins results in acetylation of E2A proteins themselves. Here we map the acetylated lysine residues within the oncogenic portion of E2A proteins and begin to elucidate some functional correlates of E2A acetylation. Our results indicate that the isolated AT domain of p/CAF as well as full-length p/CAF were capable of acetylating E2A. Interestingly, full-length p300 was capable of acetylating E2A while an isolated AT domain was unable to acetylate E2A, suggesting that additional domains of CBP/p300 are required to mediate E2A acetylation. We demonstrate that both p300 and p/CAF can interact directly with E2A, independent of the known interaction between p300 and p/CAF. These co-activators do, however, appear to co-operate to achieve maximal E2A acetylation. Mutagenesis-based mapping studies indicate that several lysines are substrates for acetylation. Of particular interest, a conserved lysine residue (K34) located within the N-terminal transcriptional activation domain (AD1) is acetylated in vitro by p/CAF. K34 is located within a GKXXP consensus sequence, suggested to be a recognition motif for acetylation by several AT enzymes including CBP/p300 and p/CAF. Conservative replacement of K34 with arginine (i.e., K43R) substantially impairs transcriptional activation of a luciferase reporter gene by E2A, suggesting that post-translational modification of this residue may play an important functional role. Consistent with a role for acetylation, relative to some other lysine-dependent modification, we were unable to demonstrate sumoylation or ubiquitination of the N-terminus of E2A. Therefore, we have found that acetylation by AT/co-activator proteins contributes to transcriptional regulation by the functionally critical N-terminal activation domain (AD1) of E2A proteins. The mechanisms by which this acetylation event is regulated and how it contributes to target gene induction by E2A are not clear. It seems plausible that the acetylation status of AD1 could be determined by upstream signaling events and acetylation of E2A could modulate interactions with transcriptional co-regulators, DNA or chromatin. Further studies to investigate these possibilities are underway. In particular, results using an amino acid substitution that mimics acetylation of AD1 (K34Q) will be presented.
Decitabine and Vitamin D3 Differentially Increase C-Jun, PU.1, and Sp1 Hematopoietic Transcription Factors To Induce Monocytic Differentiation.
Authors: Koschmieder Steffen , Agrawal Shuchi , Radomska Hanna S. , Huettner Claudia S. , Tenen Daniel G. , Ottmann Oliver G. , Berdel Wolfgang E. , Serve Hubert L. , Mueller-Tidow Carsten 
Published: October 2019

Abstract
Standard chemotherapy is not curative for many patients with acute myeloid leukemia (AML). New treatment strategies combining demethylating agents, such as decitabine, and drugs that induce myelomonocytic differentiation (i.e. Vitamin D3) may reestablish functional hematopoiesis in these patients.
We studied the effects of decitabine alone or in combination with Vitamin D3 (VD3) on promonocytic U937 cells and Ficoll-enriched blast cells from patients with AML and analyzed their impact on cell growth and viability (assessed by trypan blue exclusion), surface marker expression (FACS analysis of CD11b, C14), and the expression and function of target molecules (Northern blot, Western blot, EMSA). Doses ranging from 0.1 to 1 uM of decitabine induced CD11b and CD14 surface expression 3- to 18-fold and 3- to 4-fold, respectively. 3 to 100nM of VD3 induced CD11b and CD14 expression 1.5- to 10-fold and CD14 1.5- to 8-fold, resp. Interestingly, decitabine synergized with VD3 to increase CD11b and CD14 surface marker expression up to 73-fold and 11-fold, resp., and to induce morphologic differentiation of U937 cells along the monocytic lineage. The mechanisms of decitabine- and VD3-induced monocytic differentiation are currently unclear. Therefore, we investigated the effects of the two drugs on several transcription factors that have been implicated in monocytic differentiation. Northern and Western blotting showed that decitabine induced transcription of c-jun but not PU.1, while VD3 increased PU.1, IRF8, and C/EBPbeta but not c-jun. Monocytic target promoters such as the CD11b promoter have been shown to be activated by a complex containing PU.1 and c-jun. Using electromobility shift assays, we now demonstrate increased DNA binding of nuclear proteins from decitabine- and VD3-induced U937 cells to the CD11b promoter. In addition to the effects seen with the CD11b promoter, we investigated whether the myeloid transcription factor Sp1 played a role in decitabine- and VD3-induced CD14 expression. Indeed, we found that mithramycin A, a specific inhibitor of Sp1, inhibited both VD3- and decitabine-induced upregulation of CD14, which is in line with previous data showing that Sp1 is critical for CD14 promoter activity. Induction of CD11b and/or CD14 by decitabine and/or VD3 was confirmed in primary AML patient samples at the time of diagnosis.
In conclusion, decitabine synergizes with Vitamin D3 to induce CD11b and CD14 expression, likely by enhancing PU.1/c-jun and Sp1 transcriptional activity.
Rexinoid-Triggered Differentiation and Tumor-Selective Apoptosis of AML by Protein Kinase A-Mediated De-Subordination.
Authors: Schiavone Ettore Mariano , Altucci Lucia , De Simone Mariacarla , Ferrara Felicetto , Rossin Aurélie , Hirsch Oliver , Nebbioso Angela , Vitoux Dominique , Wilhelm Emmanuelle , Guidez Fabien , Zelent Arthur , Grimwade David , de Thé Hugues , Gronemeyer Hinrich 
Published: October 2019

Abstract
Apart from PML-RARα acute promyelocytic leukemia all other acute myeloid leukemias (AML) are unresponsive to retinoid differentiation therapy. However, in our study we show that elevating the levels of cyclic AMP (cAMP) confers onto retinoid X receptor (RXR)-selective agonists (“rexinoids”) the ability to induce terminal granulocyte differentiation and apoptosis of all-trans retinoic acid-resistant and insensitive AML cell lines and patients’ AML blasts. Protein kinase A activation leads to co-repressor release from the RAR subunit of the RAR-RXR heterodimer, resulting in “de-subordination” of otherwise silent RXR, which acquires transcriptional competence in response to cognate ligands. Rexinoid-cAMP induction of endogenous RARβ is blunted in mouse embryo fibroblasts lacking RARs, but re-introduction of exogenous RARα re-establishes responsiveness, thus confirming that the RARα-RXR heterodimer is the rexinoid mediator. The apoptogenic effect of this treatment involves enhanced expression of the death receptor DR5 and its cognate ligand, the tumor necrosis factor-related apoptosis inducing ligand (TRAIL), both of which are known to induce apoptosis in a tumor cell-selective manner and lead to the activation of initiator caspases. Immunohistochemistry confirmed induction of TRAIL and DR5 in AML patient blasts cultured “ex vivo”. AML patients’ blasts responded to rexinoid-cAMP combination treatment with induction of maturation and apoptosis, independent of karyotype, immunophenotype, and FAB classification. Clonogenic assays revealed complete inhibition of blast clonogenicity in four out of five tested samples. Indeed, it is known that cAMP levels can be elevated also by treating cells with 3′, 5′-cAMP phosphodiesterase inhibitors (PDEi’s). These observation and the clinical availability of the corresponding drugs provide a rationale for initiating clinical studies addressing the efficacy of combinatorial PDEi-rexinoid therapy in AML patients. Together with our recent finding that a very promising class of epigenetic anti-tumor drugs operates through activation of TRAIL expression (Nat Med2005, 11(1):7784), the possibility to target both the ligand (TRAIL) by HDAC inhibitors and the cognate receptors (DR4, DR5) by the above described rexinoid crosstalk may represent a promising therapeutic option which might lead, despite the genetic, morphologic, and clinical variability of AML, to a novel therapeutic option for AML patients by inducing a tumor-selective death pathway.
Rig-G Protein Links Retinoid and Interferon Signal Pathways To Inhibit Cell Cycle through Increased p27 and p21 Protein Levels.
Authors: Tong Jian-Hua , Xiao Shu , Li Dong , Zhu Hai-Qing , Song Man-Gen , Jia Pei-Min , Pan Xiao-Rong , Chen Sai-Juan , Chen Zhu 
Published: October 2019

Abstract
Over the last two decades, the molecular mechanisms of all trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells have been greatly explored The Rig-G gene was first isolated from an ATRA-treated APL cell line NB4. The expression of Rig-G was undetectable in untreated NB4 cells, but could be dramatically induced by ATRA treatment. Interestingly, database research showed that Rig-G represented a member of interferon-inducible (IFI) gene family. Moreover, a synergistic induction of Rig-G mRNA in NB4 cells by ATRA and interferons (IFNs) indicated a possible role of Rig-G in crosstalk between these two signaling pathways. In this work, we show that Rig-G is indeed a direct target of STAT1 protein, a critical transcription factor in regulating IFN responses, and involved in both ATRA and interferon pathways. By stable transfection of Rig-G in U937 cells, we find that Rig-G protein can significantly accumulate the cells at G1/S transition and inhibit cell proliferation through enhancing some important cell cycle regulators. Further studies demonstrate that Rig-G can physically interact with JAB1 (Jun activating domain binding protein). It can decrease JAB1-enhanced AP-1 transactivities through preventing JAB1 from entering the nucleus, and impair JAB1-dependent p27 nuclear export and degradation, resulting in a nuclear accumulation of p27. In addition, we show that Rig-G can also downregulate c-Myc followed by an upregulation of p21, another major negative player of cell growth. Taken together, it seems that Rig-G may be one of the first experimentally proven molecular mediators responsible for IFNs-dependent growth-suppressive responses, and it can link both IFN- and ATRA-triggered intracellular pathways to synergistically inhibit cell growth in many cell types.
Effect of Germline Polymorphisms on Clinical Outcome in Hodgkin’s Lymphoma (HL).
Authors: Gaya Anna , Urbano-Ispizua Alvaro , Navarro Alfons , Pons Aina , Abrisqueta Pau , Martinez Carmen , Granell Miquel , Martinez Antonio , Lopez-Guillermo Armando , Montserrat Emili , Monzo Mariano 
Published: October 2019

Abstract
In this study, we investigated whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways (GSTT1, GSTP1, GSTM1, SULT1C2, TOP2A, SXR-1), DNA repair (XPD, XPA, ERCC1, ERCC5, XRCC1, XRCC4, XRCC5), apoptosis and inflammatory cytokines (FAS, FASL, IL-10), and multidrug resistance (MDR1-2, MDR1-6) predict clinical outcome in patients with HL. One hundred and twenty-seven adult patients (median age, 33 yrs; range, 15–80; males 53%) diagnosed with HL at a single institution between September 1995 and June 2005 have been studied. Seventeen patients (13.4%) were HIV+. Distribution according to histological subtypes was: nodular sclerosis (56.7%), mixed cellularity (20.5%), lymphocytic predominance (5.6%), and lymphoid depletion (5.6%). Epstein-Barr Virus (EBV) was present in 35.4% of the samples. First-line treatment consisted of CMOPP/ABV (39.4%) or ABVD (52.8%). Allelic discrimination of single nucleotide polymorphisms (SNPs) (ABI Prism 7500; TaqMan) of DNA obtained from formalin fixed paraffin embedded lymph nodes was performed. The characteristics considered were: age (<45 years vs. ≥45), ECOG, Hasenclever prognostic index (≤1 vs 2–4 vs ≥5), HIV status, Ann Arbor (I–II vs. III–IV), WHO histological classification, bulky disease, EBV (LMP1+ vs LMP1−), ESR (EORTC criteria), and polymorphisms of the above-mentioned genes. Clinical outcomes analyzed were probability to achieve complete remission (CR), toxicity due to the treatment, relapse rate, disease-free survival (DFS) and overall survival (OS). Out of 127 patients, 101 (79.5%) achieved CR, 7 (5.5%) partial response, 9 (7.1%) were chemoresistant, and 5 (3.9%) died during the initial treatment. After a median follow-up of 43 months (1–128), OS was 81.1% and DFS 62.6%. In the multivariate analysis, the only adverse prognostic factor for the achievement of CR was FASL -844 T>C polymorphism (RR=1.7; p=0.01) and the only adverse prognostic factor for relapse was IL-10 -1082 A>G polymorphism (RR=2.1; p=0.02). A lower probability of DFS was associated with HIV+ status (RR=11.4; p=0.03), and a lower probability of OS to higher Hasenclever prognostic index (RR=2.3; p=0.02). Moreover, a close association between Asp5Glu genotype of the phase II drug-metabolizing enzyme SULT1C2 and pulmonary toxicity was found; thus, all eight patients with pulmonary toxicity due to bleomicine had the wild type SULT1C2 genotype (p=0.006). In conclusion, germline polymorphisms in FASL, IL-10 and SULT1C2, which can easily be analyzed in paraffin embedded samples, have prognostic value in patients with HL.
Absolute Lymphocyte Count Is a Novel Prognostic Indicator in Acute Leukemia: Implications for Risk Stratification and Future Studies.
Authors: De Angulo Guillermo R. , Yuen Carrie , Palla Shana , Anderson Peter M. , Zweidler-McKay Patrick A. 
Published: October 2019

Abstract
Background: Despite improving outcomes, 25–50% of children and young adults with acute leukemia still relapse and most salvage rates are discouraging. Additional prognostic factors, particularly those that represent host factors, may further stratify patients and decrease relapse rates.
Purpose: To determine if absolute lymphocyte counts (ALC) during induction chemotherapy can improve current risk stratification and predict relapse-free survival (RFS) and overall survival (OS) in children and young adults with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods: We analyzed 160 consecutive cases of de novo ALL and AML patients 1–21 years of age, treated at the University of Texas M. D. Anderson Cancer Center from 1995–2005. Age at diagnosis, initial WBC, bone marrow blast % on days 0 and 7, were analyzed with ALC on days 0, 15, 21 and 28 of induction therapy.
Results: ALC during induction therapy is a significant independent predictor of RFS and OS in young adults and children with either ALL or AML. Specifically, an ALC <350 cells/mcL on day 15 of induction therapy for ALL significantly predicts poor 6-year OS (52% vs. 87%, p=0.015; HR=4.2, Figure 1A) and RFS (46% vs. 80%, p=0.001; HR=4.8, Figure 1B). Similarly, an ALC of <350 cells/mcL on day 15 of induction therapy for AML predicts poor 6-year OS (35% vs. 86%, p=0.033; HR=4, Figure 1C). ALC-15 remains a significant predictor of OS and RFS after adjusting for age at diagnosis, initial WBC and bone marrow response on day 7 (p=0.013; HR=6.3, and p=0.003; HR=6.3, respectively) in multivariate analysis (Table 1). Importantly, ALC-15 defines a subgroup of half of our AML patients and predicts an excellent 5-year OS of 86% (p=0.033, Figure 1C). Conversely, prolonged lymphopenia predicts that 16% of young AML patients will have a dismal 5-year RFS of 14% (p=0.004, Figure 1D). Finally, ALC-15 <350 cells/mcL is able to predict 70% of relapses in both ALL and AML patients. One possible algorithm could identify half of AML patients with a predicted OS of 86% simply by measuring the ALC-15. Those patients with a low ALC on day 15 would be assessed at day 21 and 28 and those with persistent lymphopenia would be predicted to to have an RFS of 14% and would be stratified to receive intensified and/or experimental therapy.
Conclusion: We demonstrate that ALC can identify patients at high and low risk for relapse early in the course of treatment for ALL or AML. Our data indicates that ALC is both independent of and a more powerful predictor than age at diagnosis, initial WBC and bone marrow response on day 7. This routine measurement could enhance current risk-stratification and lead to improved outcomes in young patients with acute leukemias.
Figure 1 Figure 1. Table 1 Multivariate Analysis of ALC, Age, WBC, Bone marrow response and Survival
The Gene Expression Profile of T-Cell Prolymphocytic Leukemia with inv(14)(q11q32) Reflects the Pattern of Chromosomal Imbalances.
Authors: Dürig Jan , Bug Stefanie , Klein-Hitpass Ludger , Boes Tanja , Jöns Thomas , Dührsen Ulrich , Siebert Reiner 
Published: October 2019

Abstract
T-cell prolymphocytic leukemia (T-PLL) is an aggressive lymphoma derived from mature T-cells, which is in most cases characterized by the presence of an inv(14)(q11q32) and a characteristic pattern of secondary chromosomal aberrations. DNA microarray technology was employed to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor derived peripheral blood cells with five highly purified inv(14)-positive T-PLL blood samples. In comparison between the two experimental groups 740 genes were identified as differentially expressed including functionally important genes involved in lymphomagenesis, cell cycle regulation, apoptosis and DNA repair. Notably, the differentially expressed genes were found to be significantly enriched in genomic regions affected by recurrent chromosomal imbalances. Up-regulated genes clustered significantly on chromosome arms 6p and 8q and down-regulated genes on 6q, 8p, 10p, 11q and 18p. High-resolution copy-number determination using SNP-chip technology in twelve inv(14)/t(14;14)-positive T-PLL including those analyzed for gene expression refined chromosomal breakpoints as well as regions of imbalances. In conclusion, combined transcriptional and molecular cytogenetic profiling identified novel specific chromosomal loci and genes which are likely to be involved in disease progression and suggests a gene dosage effect as a pathogenic mechanism in T-PLL.