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Berlin Brandenburg

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  • 1
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.1912-1912
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 January 2013, Vol.110(3), pp.1041-1046
    Description: The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, wholetranscriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU. 1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
    Keywords: Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Physiology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Cancer Research, 07/01/2017, Vol.77(13 Supplement), pp.299-299
    ISSN: 0008-5472
    E-ISSN: 1538-7445
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  • 4
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.375-375
    ISSN: 0008-5472
    E-ISSN: 1538-7445
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  • 5
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.915-915
    Description: Introduction: Human bone marrow aging is typified by decreased cellularity, stem cell exhaustion and myeloid lineage bias that may set the stage for development of myeloid malignancies. Secondary AML (sAML) is a malignancy that has been associated with alterations in RNA processing genes and currently has few effective treatment options available. A central goal of future therapeutic strategies is to prevent disease relapse and therapeutic resistance by selectively targeting unique gene products that are essential to LSC but not normal HSC function. Therefore, we established whole gene, long non-coding RNA (lncRNA), splice isoform, and RNA editing signatures of benign versus malignant bone marrow progenitor cell aging, and evaluated the therapeutic efficacy of splicing-targeted agents in pre-clinical humanized in vitro and in vivo model systems.
    Keywords: Isoforms ; Acute Myeloid Leukemia ; Aging ; Bone Marrow ; Non-Coding RNA ; Developmental Stages ; Cancer ; RNA Processing ; Leukemia ; Stem Cells ; Malignancy ; Splicing ; Osteoprogenitor Cells ; RNA Editing ; Benign ; RNA ; Cancer Immunology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: Trends in Molecular Medicine, September 2015, Vol.21(9), pp.549-559
    Description: ADAR (adenosine deAminase acting on RNA) editases catalyze the deamination of adenosine to inosine (A-to-I), a post-transcriptional modification that alters coding and non-coding RNA stability and function. ADAR editases such as ADAR1 have recently been shown to play a key role in normal stem cell maintenance. While ADAR mutations are associated with hereditary autoimmune diseases such as Aicardi–Goutières syndrome, ADAR copy-number alterations and editase activation have been associated with progression of a broad array of malignancies. In this review we discuss evidence linking aberrant A-to-I editing to cancer and other degenerative diseases, and the mechanisms that may be targeted by novel therapeutic strategies.
    Keywords: RNA Editing ; Human Disease ; Adar ; Degenerative Disease ; Medicine ; Biology
    ISSN: 1471-4914
    E-ISSN: 1471-499X
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  • 7
    Language: English
    In: BMC Cancer, 01 June 2011, Vol.11(1), p.244
    Description: Abstract Background Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. Methods We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). Results A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. Conclusions ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches aimed to study genes or pathways involved in ccRCC etiopathogenesis and to identify novel clinical markers or therapeutic targets. Moreover, SNP array technology proved to be a powerful tool to better define the cell composition and homogeneity of RCC primary cultures.
    Keywords: Medicine
    ISSN: 1471-2407
    E-ISSN: 1471-2407
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  • 8
    Language: English
    In: BMC Cancer, June 13, 2011, Vol.11, p.244
    Description: Background Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. Methods We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). Results A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. Conclusions ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches aimed to study genes or pathways involved in ccRCC etiopathogenesis and to identify novel clinical markers or therapeutic targets. Moreover, SNP array technology proved to be a powerful tool to better define the cell composition and homogeneity of RCC primary cultures.
    Keywords: Genomes -- Physiological Aspects ; Genomes -- Research ; Renal Cell Carcinoma -- Development And Progression ; Renal Cell Carcinoma -- Genetic Aspects ; Renal Cell Carcinoma -- Research ; Dna -- Physiological Aspects ; Dna -- Research
    ISSN: 1471-2407
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: BMC Cancer, June 13, 2011, Vol.11, p.244
    Description: Background Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. Methods We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). Results A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. Conclusions ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches aimed to study genes or pathways involved in ccRCC etiopathogenesis and to identify novel clinical markers or therapeutic targets. Moreover, SNP array technology proved to be a powerful tool to better define the cell composition and homogeneity of RCC primary cultures.
    Keywords: Genomes -- Physiological Aspects ; Genomes -- Research ; Renal Cell Carcinoma -- Development And Progression ; Renal Cell Carcinoma -- Genetic Aspects ; Renal Cell Carcinoma -- Research ; Dna -- Physiological Aspects ; Dna -- Research
    ISSN: 1471-2407
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: Journal of Translational Medicine, Feb 12, 2015, Vol.13(1)
    Description: Background Deregulation of RNA editing by adenosine deaminases acting on dsRNA (ADARs) has been implicated in the progression of diverse human cancers including hematopoietic malignancies such as chronic myeloid leukemia (CML). Inflammation-associated activation of ADAR1 occurs in leukemia stem cells specifically in the advanced, often drug-resistant stage of CML known as blast crisis. However, detection of cancer stem cell-associated RNA editing by RNA sequencing in these rare cell populations can be technically challenging, costly and requires PCR validation. The objectives of this study were to validate RNA editing of a subset of cancer stem cell-associated transcripts, and to develop a quantitative RNA editing fingerprint assay for rapid detection of aberrant RNA editing in human malignancies. Methods To facilitate quantification of cancer stem cell-associated RNA editing in exons and intronic or 3'UTR primate-specific Alu sequences using a sensitive, cost-effective method, we established an in vitro RNA editing model and developed a sensitive RNA editing fingerprint assay that employs a site-specific quantitative PCR (RESSq-PCR) strategy. This assay was validated in a stably-transduced human leukemia cell line, lentiviral-ADAR1 transduced primary hematopoietic stem and progenitor cells, and in primary human chronic myeloid leukemia stem cells. Results In lentiviral ADAR1-expressing cells, increased RNA editing of MDM2, APOBEC3D, GLI1 and AZIN1 transcripts was detected by RESSq-PCR with improved sensitivity over sequencing chromatogram analysis. This method accurately detected cancer stem cell-associated RNA editing in primary chronic myeloid leukemia samples, establishing a cancer stem cell-specific RNA editing fingerprint of leukemic transformation that will support clinical development of novel diagnostic tools to predict and prevent cancer progression. Conclusions RNA editing quantification enables rapid detection of malignant progenitors signifying cancer progression and therapeutic resistance, and will aid future RNA editing inhibitor development efforts. Keywords: Cancer stem cells, Leukemia stem cells, RNA editing, Biomarkers, Leukemia, ADAR1
    Keywords: Cancer – Prevention ; Cancer – Development and Progression ; Drug Resistance – Prevention ; Drug Resistance – Development and Progression
    ISSN: 1479-5876
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