Expanding The TLX1-Regulome In T Cell Acute Lymphoblastic Leukemia Towards Long Non-Coding RNAs

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 813-813
Author(s):  
Kaat Durinck ◽  
Joni Van der Meulen ◽  
Maté Ongenaert ◽  
Pieter-Jan Volders ◽  
Annelynn Wallaert ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Protein Coding ◽  
Chip Sequencing ◽  
Lncrna Expression ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Non Coding Rnas

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that results from the malignant transformation of T-cell precursors and affects children, adolescents and adults. In T-ALL, genetic lesions in several possible oncogenes and tumor suppressors have been shown to cooperatively contribute to leukemogenesis. The TLX1 (T-cell leukemia homeobox protein-1, HOX11) oncoprotein is aberrantly expressed in in 5-10% of pediatric patients and 30% of adult T-ALL patients due to chromosomal translocations. Although many downstream protein coding targets genes of TLX1 have been identified, the non-coding network downstream of TLX1 remains elusive. In this study we expand the TLX1 regulome towards long non-coding RNAs (lncRNAs). Hereto we measured the transcriptional response of all protein coding genes and 12,000 lncRNAs following TLX1 knock down in the ALL-SIL cell line using a custom designed mRNA/lncRNA expression platform (Agilent). In addition, similar mRNA-lncRNA expression profiles of 64 primary T-ALL patient samples were generated which included five TLX1+ cases. To establish the direct transcriptional TLX1 targets, we generated TLX1 ChIP-sequencing data from ALL-SIL leukemic cells. We confirm direct regulation of previously established protein coding gene targets and de novo TLX1 motif discovery also identified RUNX1 as an important mediator of the global TLX1 transcriptional network (Della Gatta et al., Nature Medicine, 2012). Complementary to these data, our analysis for the first time establishes the TLX1 driven lncRNAome in thymocyte derived leukemic cells. Remarkably, the majority of TLX1 controlled lncRNAs were upregulated suggesting that they may be implicated in the TLX1 driven repression of protein coding gene expression. Finally, pairwise mRNA-lncRNA correlation analysis allowed functional annotation of TLX1 targeted lncRNAs. In conclusion, we present the first landscaping of the genome-wide binding pattern of TLX1 and provide evidence for a previously unestablished role of lncRNAs in the TLX1 regulatory network. Disclosures: No relevant conflicts of interest to declare.

scholarly journals DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

2021 ◽  
Vol 22 (3) ◽  
pp. 1388
Author(s):  
Natalia Maćkowska ◽  
Monika Drobna-Śledzińska ◽  
Michał Witt ◽  
Małgorzata Dawidowska
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Global Methylation ◽  
Current State ◽  
History Of ◽  
Cell Acute Lymphoblastic Leukemia

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

Abstract In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

scholarly journals Does activation of the TAL1 gene occur in a majority of patients with T- cell acute lymphoblastic leukemia? A pediatric oncology group study

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 666-676 ◽  
Author(s):  
RO Bash ◽  
S Hall ◽  
CF Timmons ◽  
WM Crist ◽  
M Amylon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Leukemic Cells ◽  
Monoallelic Expression ◽  
Regulatory Sequences ◽  
Cis Acting ◽  
Polymorphic Dinucleotide ◽  
Cell Acute Lymphoblastic Leukemia

Almost 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL) have tumor-specific rearrangements of the TAL1 gene. Although TAL1 expression has not been observed in normal lymphocytes, TAL1 gene products are readily detected in leukemic cells that harbor a rearranged TAL1 allele. Hence, it has been proposed that ectopic expression of TAL1 promotes the development of T-ALL. In this report, we show that TAL1 is expressed in the leukemic cells of most patients with T-ALL, including many that do not display an apparent TAL1 gene alteration. A polymorphic dinucleotide repeat in the transcribed sequences of TAL1 was used to determine the allele specificity of TAL1 transcription in primary T-ALL cells. Monoallelic expression of TAL1 was observed in the leukemic cells of all patients (8 of 8) bearing a TAL1 gene rearrangement. In the leukemic cells of patients without detectable TAL1 rearrangements, TAL1 transcription occurred in either a monoallelic (3 of 7 patients) or a biallelic (4 of 7 patients) fashion. Thus, TAL1 activation in these patients may result from subtle alterations in cis-acting regulatory sequences (affecting expression of a single TAL1 allele) or changes in trans-acting factors that control TAL1 transcription (affecting expression of both TAL1 alleles).

scholarly journals The NOTCH1 Driven Long Non-Coding RNA Repertoire in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 900-900
Author(s):  
Annelynn Wallaert ◽  
Kaat Durinck ◽  
Pieter Rondou ◽  
Inge van de Walle ◽  
Wouter Vanloocke ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Gene Set Enrichment Analysis ◽  
Protein Coding ◽  
Gene Set ◽  
Notch1 Signaling ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Individual

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer resulting from the malignant transformation of T-cell precursors. Genetic studies in T-cell acute lymphoblastic leukemia (T-ALL) have uncovered a remarkable heterogeneity of genetic defects. Amongst these, NOTCH1activating mutations are the most frequently occurring events (>50%) in T-ALL. Since long non-coding RNAs (lncRNAs) are emerging as important players in oncogenesis, we decided to decode the NOTCH1 driven lncRNA transcriptional landscape in T-ALL and normal T-cell development. Methods and Results: RNA-sequencing was performed following pharmacological inhibition (GSI) of the NOTCH1 mutant and gamma secretase inhibitor (GSI) sensitive T-ALL cell line CUTLL1 in a time series experiment as well as for human CD34+ thymic progenitor T-cells cultured on an OP9 feeder layer with or without DL1-triggered NOTCH1 stimulation. First, we validated both model systems by confirming robust regulation of multiple canonical known protein coding NOTCH1 target genes including DTX1, NOTCH3 and NRARP. Next, we identified distinct subsets of NOTCH1 regulated lncRNAs in both experiments with an overlap of 27 commonly regulated NOTCH1 driven and previously annotated lncRNAs. An even larger number of novel, unannotated T-ALL/T-cell specific lncRNAs was found to be NOTCH1 regulated. Next, we took advantage of publically available ChIP-sequencing data for ICN1 and enhancer specific chromatin marks in CUTLL1 (Wang et al., PNAS, 2013), allowing the selection for direct regulated lncRNAs with enhancer properties. Amongst these lncRNAs, the recently described LUNAR1 lncRNA (Trimarchi et al., Cell, 2014) was present as top candidate in our dataset, thus validating this approach for further selecting bona fide NOTCH1 regulated lncRNAs. In a first step towards functional annotation of this subset of selected lncRNAs, we performed so-called guilt-by-association analysis through correlating expression levels of the individual lncRNAs with transcriptome data for all protein coding genes followed by gene set enrichment analysis in a large cohort of primary T-ALL patients. Subsequent enrichment mapping of significant gene sets yielded markedly different gene set clustering patterns for each of the individual analyzed lncRNAs, as well as distinct annotated related functionalities such as cytokine signaling, TCA-cycle, DNA replication and repair and translation. Prioritarization of lncRNAs for further functional validation was performed by measuring their expression in an extended panel of GSI-treated T-ALL cell lines (HPB-ALL, DND-41, T-ALL1 and ALL-SIL), sorted subsets of CD34+ and CD4+/CD8+ double positive thymocytes and an independent T-ALL patient cohort. Conclusion: We present the landscaping of an integrated lncRNA network acting downstream of NOTCH1 signaling in T-ALL and normal T-cells. These data pave the way towards the development of novel therapeutic strategies impacting on hyperactive NOTCH1 signaling. Disclosures No relevant conflicts of interest to declare.

Telomeres and Telomerase in Pediatric Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4389-4389
Author(s):  
Johann Greil ◽  
Elke Kleideiter ◽  
Matthias Schwab ◽  
Petra Boukamp ◽  
Ewa Koscielniak ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Clinical Outcome ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Telomerase Activity ◽  
Leukemic Cells ◽  
Htert Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Shortened telomeres and elevated levels of telomerase activity are apparently characteristic features of hematologic neoplasias such as high-grade lymphomas and relapsing leukemia. Thus, their measurement might be useful for monitoring disease conditions or predicting clinical outcome. In order to investigate the potential of telomere length (TRF) and telomerase activity (TA) as prognostic indicator in pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) we analyzed TRF and TA in samples from 20 patients (age range 2–17.5 years). In addition, as TA is limited by the expression of the telomerase catalytic subunit (hTERT) we analyzed hTERT expression. We found that TRF varied widely (3.5 – 8.1 kb; mean ± SD: 6.4 +/− 1.3 kb) in leukemic cells and was significantly shorter (p<0.0001) than that of age-matched controls (8.3 ± 0.4 kb; n=19). Elevated levels of TA were present in 95% of the leukemic samples. Furthermore, expression of hTERT demonstrated a wide interindividual variability (range 141–424,000 normalized units). A statistically significant association between TA and hTERT expression was not found and TRF, TA and hTERT expression was not associated with the clinical outcome in pediatric T-ALL, thereby limiting their prognostic significance.

Inv(11)(q21q23) Fuses MLL to the NOTCH Co-Activator Mastermind-Like 2 in Secondary T Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4284-4284
Author(s):  
Markus Metzler ◽  
Jan Zuna ◽  
Martin S. Staege ◽  
Lana Harder ◽  
Claus Meyer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transcriptional Activation ◽  
Selection Process ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Fusion Partner ◽  
Secondary Leukemia ◽  
Transcriptional Activation Domain ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Development of a secondary leukemia after chemotherapeutic treatment for childhood acute leukemia is associated with rearrangements of the MLL gene on chromosome 11q23 and characteristically results in acute myeloid leukemia (AML). We identified the NOTCH co-activator Mastermind-like 2 as MLL fusion partner in two cases of pediatric secondary leukemia. The MLL-MAML2 fusion results from a cryptic inv(11)(q21q23) only detectable by interphase fluorescence in situ hybridization with an MLL split signal probe. With a latency of twenty months and five years after initial diagnosis for MLL negative AML and precursor B acute lymphoblastic leukemia (ALL), respectively, both patients developed a therapy-related T-cell acute lymphoblastic leukemia. MAML2 is the first MLL fusion partner involved in human Notch-signaling and was only recently identified as recurrent translocation fusion partner in a subset of salivary gland tumors. The genomic MLL breakpoint shows similar localization and sequence features described for etoposide induced treatment-related AML. MLL-MAML2 positive cells were detectable up to two years prior to clinical apparent secondary leukemia in one case. The discrepant dynamics of clone expansion quantified by either the genomic fusion sequence or Ig/TCR gene rearrangements as clone specific markers suggests a selection process within the inversion positive population and the need for additional mutation events to promote overt leukemic disease. Whole genome expression profiles demonstrated differential expression of both typical MLL and NOTCH downstream genes, which suggests a modulatory role of the MAML2 transcriptional activation domain in MLL leukemogenesis and lineage assignment induced by the MLL-MAML2 fusion protein. MSM21620813 WSF3401600.

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

TGF-β induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6695-6698 ◽  
Author(s):  
Jean-Michel Terme ◽  
Ludovic Lhermitte ◽  
Vahid Asnafi ◽  
Pierre Jalinot
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Lymphoblastic Leukemia ◽  
Transforming Growth Factor Β ◽  
Leukemic Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Ubiquitin Proteasome ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Proteasome Pathway

Abstract T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor β (TGF-β), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-β and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.

scholarly journals The evolution of relapse of adult T cell acute lymphoblastic leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Inés Sentís ◽  
Santiago Gonzalez ◽  
Eulalia Genescà ◽  
Violeta García-Hernández ◽  
Ferran Muiños ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Leukemic Cells ◽  
Driver Mutations ◽  
Pediatric Malignancy ◽  
Genetic Mechanisms ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Moment

Abstract Background Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

scholarly journals Cell of origin strongly influences genetic selection in a mouse model of T-ALL

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4646-4656 ◽  
Author(s):  
Katherine E. Berquam-Vrieze ◽  
Kishore Nannapaneni ◽  
Benjamin T. Brett ◽  
Linda Holmfeldt ◽  
Jing Ma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Genetic Selection ◽  
Sleeping Beauty ◽  
Cell Of Origin ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Identifying the normal cell from which a tumor originates is crucial to understanding the etiology of that cancer. However, retrospective identification of the cell of origin in cancer is challenging because of the accumulation of genetic and epigenetic changes in tumor cells. The biologic state of the cell of origin likely influences the genetic events that drive transformation. We directly tested this hypothesis by performing a Sleeping Beauty transposon mutagenesis screen in which common insertion sites were identified in tumors that were produced by mutagenesis of cells at varying time points throughout the T lineage. Mutation and gene expression data derived from these tumors were then compared with data obtained from a panel of 84 human T-cell acute lymphoblastic leukemia samples, including copy number alterations and gene expression profiles. This revealed that altering the cell of origin produces tumors that model distinct subtypes of human T-cell acute lymphoblastic leukemia, suggesting that even subtle changes in the cell of origin dramatically affect genetic selection in tumors. These findings have broad implications for the genetic analysis of human cancers as well as the production of mouse models of cancer.

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