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  • 1
    Online Resource
    Online Resource
    Identification of Key microRNAs As Predictive Biomarkers of Nilotinib Response in Chronic Myeloid Leukemia: A Sub-Analysis of the Enestxtnd Clinical Trial
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 12169-12170
    Details
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 12169-12170
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2022-168534
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia
    American Society of Hematology ; 2021
    In:  Blood Vol. 137, No. 26 ( 2021-07-01), p. 3641-3655
    Details
    In: Blood, American Society of Hematology, Vol. 137, No. 26 ( 2021-07-01), p. 3641-3655
    Abstract: The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020007651
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 3
    Online Resource
    Online Resource
    Circular RNAs of the Nucleophosmin 1 (NPM1) Gene in Acute Myeloid Leukemia Patients
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2695-2695
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2695-2695
    Abstract: Background: The nucleophosmin 1 (NPM1) gene is not only commonly mutated in acute myeloid leukemia (AML), but also encodes several linear splice isoforms, one of which was recently shown to be of prognostic importance. Furthermore, circular RNAs (circRNAs) are transcribed from the NPM1 gene which demands further investigation with regard to function in normal hematopoiesis and impact on leukemogenesis. Aims: We aimed to investigate circRNAs derived from NPM1 and gain insights into their regulation and function. Additionally, we wanted to determine changes in the circular RNAome in the course of hematopoietic differentiation and leukemic transformation. Methods: Circular NPM1 transcripts were detected by PCR and sequenced in leukemic cell lines (n=7) and healthy control samples (n=3, peripheral blood-derived mononuclear cells). Expression of hsa_circ_0075001 and total NPM1 was measured in a cohort of 23 NPM1 wildtype (NPM1wt) and 23 NPM1 mutated (NPM1mut) AML patients via quantitative real-time PCR (qPCR), and Affymetrix U133plus2 microarray data was set in relation to the expression levels. Principal component analysis (PCA) was conducted to identify groups with similarities in gene expression patterns and differentially expressed genes were subjected to pathway analysis. Next, ribosomal RNA-depleted RNA-seq was performed for 5 NPM1mut and 5 NPM1wt AML cases, as well as 10 healthy control samples derived from 4 FACS-sorted myeloid differentiation stages (myeloblasts, promyelocytes, metamyelocytes and neutrophils). PCA and unsupervised hierarchical clustering were performed based on circRNA expression. Results: We detected and sequenced multiple circular NPM1 transcripts (n=23) in leukemic as well as in healthy control cells. As hsa_circ_0075001 showed differential expression between different AML cell lines in a semi-quantitative PCR analysis, quantification in 46 AML patients via qPCR was performed. This analysis revealed that total NPM1 and hsa_circ_0075001 expression were independent of the NPM1 mutational status. Furthermore, the hsa_circ_0075001 expression status defined distinct leukemia subgroups characterized by similarities in gene expression as determined by PCA. For example, differentially expressed genes between high versus low hsa_circ_0075001 expression groups (dichotomized at the median) were significantly enriched in components of the Toll-like receptor (TLR) signaling pathway, which was downregulated in patients with high hsa_circ_0075001 expression. Expression of hsa_circ_0075001 correlated positively with total NPM1 expression, and RNA-seq analysis further revealed a global correlation of circRNA and parental gene expression. In total, in our cohort circRNAs were found for 19 % of all expressed genes. PCA based on circRNA expression illustrated that immature and mature hematopoietic cells, as well as NPM1wt and NPM1mut AML samples, exhibit distinct circRNA signatures (Figure 1). Thus, circRNA expression seems to play a role during differentiation of normal hematopoietic cells, but also seems to be severely deregulated in AML. Figure 1: Altered circular RNA expression in AML patients compared to healthy control samples. Principal component analysis (PCA) of circRNA expression data of 5 NPM1mut patients (red), 5 NPM1wt patients (green), and 10 healthy control samples, of which 4 were derived from immature (blue) and 6 from more mature myeloid differentiation stages (purple). Data was generated via RNA-Seq and reads derived from circRNAs were aligned and quantified using STAR, and normalized and transformed using DESeq2. PCA was performed based on 500 genes with the highest variance of circRNA expression across all samples. Conclusions: circRNAs transcribed from the NPM1 gene showed differential expression in AML cell lines and healthy cells, and higher hsa_circ_0075001 expression defined an AML subgroup characterized by downregulation of the TLR signaling pathway. These findings provide evidence for the relevance of circular NPM1 transcripts and add another level of complexity to the multifaceted gene NPM1. In general, circRNA expression seems to be involved in the regulation of hematopoietic differentiation, which is in line with previous observations, but, based on distinct circRNA expression profiles in AML, they might also play a significant pathogenic role in leukemic transformation. Figure 1 Figure 1. Disclosures Paschka: Celgene: Honoraria; Pfizer Pharma GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Medupdate GmbH: Honoraria; Novartis: Consultancy; ASTEX Pharmaceuticals: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2695.2695
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 4
    Online Resource
    Online Resource
    Identification of Previously Unrecognized Multiple Myeloma Risk Subgroups with a Novel Biological Disease Stratifier
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4718-4718
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4718-4718
    Abstract: Background: The prognosis of MM is determined by affected organs, tumor burden as measured by e.g., the international staging system (ISS), disease biology such as cytogenetic abnormalities, and response to therapy. The outcome of high-risk MM patients classified by ISS or adverse risk cytogenetics is not uniform and patients show heterogeneous survival. Recent insights into the pathogenesis of MM highlighted genome/transcriptome editing as well as inflammation as drivers for the onset and progression of MM. We hypothesized that inclusion of molecular features into risk stratification could potentially resolve the challenge of accurately distinguishing between high-risk and low-risk MM patients at initial diagnosis and improve outcome. Aim: We aimed to create a simple molecular risk score to identify unrecognized patient subgroups, who have been previously misclassified by current risk stratifiers. Method: The Multiple Myeloma Research Foundation CoMMpass study genomics dataset, combining mRNA Seq and clinical data from more than 700 MM patients, allowed us to evaluate the prognostic value of demographic and clinical parameters, cytogenetics, and gene expression levels of APOBEC genes as well as inflammation-modulating cytokines in MM patients. We calculated hazard ratios and Kaplan-Meier survival estimates for all extracted features. Combining clinical variables that were significantly associated with PFS and OS, we then applied machine learning approaches to identify the most accurate classification model to define a new risk score that is easy to compute and able to stratify NDMM patients more accurately than cytogenetics-based classifiers. Based on a Kaplan-Meier survival curve analysis, we then evaluated the performance of our newly built EI score in sub-classifying of current multiple myeloma risk stratifiers. Results: Based on machine learning models, we defined a weighted OS/PFS risk score (Editor-Inflammation (EI) score) based on mRNA expression of APOBEC2, APOBEC3B, IL11, TGFB1, TGFB3, as well as ß2-microglobulin and LDH serum levels. We showed that the EI score subclassified patients into high-risk, intermediate-risk, and low-risk prognostic groups and demonstrated superior performance (C-index: 0.76) compared to ISS (C-index: 0.66) and R-ISS (C-index: 0.64). We further showed that EI low-risk patients do not benefit from autograft and maintenance therapy. Re-classification of ISS (Figure 1a, b, c) and R-ISS risk groups further confirmed the superiority of the EI score. In addition, the EI score identified previously unrecognized distinct subgroups of MM patients with adverse risk cytogenetics but good prognosis (Figure 1d, e, f). For example, the EI score excellently subclassified del(17p) MM patients into three main risk subgroups including a super low-risk group (none of them has p53 mut) with 5-year OS of 100%, an intermediate-risk group (30% of these patients also have p53 mut) with 5-year OS rate of 75%, and a very poor prognosis group of patients (40% of these patients also have p53 mut) with 5-year OS rate of 0% (2y OS: 40%) (Figure 1f). In line, we could show that patients with del(17p) and high EI score exhibit an enrichment of APOBEC induced genomic mutations compared to intermediate-risk and low-risk patients supporting the hypothesis that del(17p) along with high APOBEC expression levels activate the APOBEC mutation program and thus create an optimal environment for tumor progression. These findings support the necessity of a prognostic score that more accurately reflects MM disease biology. Conclusion: Although MM is considered as an incurable disease, an improved risk stratification could help to identify previously unrecognized low- and high-risk patient subgroups that are over- or undertreated and lead to improved outcomes. Our EI score is a simple score that is based on recent insights into MM biology and accurately identifies high-risk and low-risk newly diagnosed MM patients as well as misclassified MM patients in different cytogenetic and ISS risk subgroups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-148718
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia
    Ferrata Storti Foundation (Haematologica) ; 2017
    In:  Haematologica Vol. 102, No. 12 ( 2017-12), p. 2039-2047
    Details
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 102, No. 12 ( 2017-12), p. 2039-2047
    Type of Medium: Online Resource
    ISSN: 0390-6078 , 1592-8721
    URL: Article
    DOI: 10.3324/haematol.2017.172866
    Language: English
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2017
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    detail.hit.zdb_id: 2030158-3
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  • 6
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    Online Resource
    P-150: Identification of misclassified multiple myeloma patient risk subgroups with a novel biological disease stratifier
    Elsevier BV ; 2022
    In:  Clinical Lymphoma Myeloma and Leukemia Vol. 22 ( 2022-08), p. S117-S118
    Details
    In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 22 ( 2022-08), p. S117-S118
    Type of Medium: Online Resource
    ISSN: 2152-2650
    URL: Article
    DOI: 10.1016/S2152-2650(22)00480-3
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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    detail.hit.zdb_id: 2193618-3
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  • 7
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    Online Resource
    Circulating microRNAs in hematological diseases: principles, challenges, and perspectives
    American Society of Hematology ; 2013
    In:  Blood Vol. 121, No. 25 ( 2013-06-20), p. 4977-4984
    Details
    In: Blood, American Society of Hematology, Vol. 121, No. 25 ( 2013-06-20), p. 4977-4984
    Abstract: The complex microRNA (miRNA) network plays an important role in the regulation of cellular processes such as development, differentiation, and apoptosis. Recently, the presence of cell-free miRNAs that circulate in body fluids was discovered. The ability of these circulating miRNAs to mirror physiological and pathophysiological conditions as well as their high stability in stored patient samples underlines the potential of these molecules to serve as biomarkers for various diseases. In this review, we describe recent findings in miRNA-mediated cell-to-cell communication and the functions of circulating miRNAs in the field of hematology. Furthermore, we discuss current approaches to design biomarker studies with circulating miRNAs. This article critically reviews the novel field of circulating miRNAs and highlights their suitability for clinical and basic research in addition to their potential as a novel class of biomarkers.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2013-01-480079
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Online Resource
    The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements
    Ferrata Storti Foundation (Haematologica) ; 2021
    In:  Haematologica Vol. 107, No. 8 ( 2021-12-02), p. 1758-1772
    Details
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 107, No. 8 ( 2021-12-02), p. 1758-1772
    Abstract: Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary samples from patients as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chromosome 3 abnormalities. Furthermore, we showed that NRIP1 knockdown negatively affects the proliferation and survival of 3qrearranged AML cells and increases their sensitivity to all-trans retinoic acid, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.
    Type of Medium: Online Resource
    ISSN: 1592-8721 , 0390-6078
    URL: Article
    DOI: 10.3324/haematol.2021.276048
    Language: Unknown
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2021
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  • 9
    Online Resource
    Online Resource
    Comprehensive micro RNA expression profiling in cerebrospinal fluid distinguishes between neurological disease classes
    Wiley ; 2019
    In:  Neuropathology and Applied Neurobiology Vol. 45, No. 3 ( 2019-04), p. 318-323
    Details
    In: Neuropathology and Applied Neurobiology, Wiley, Vol. 45, No. 3 ( 2019-04), p. 318-323
    Type of Medium: Online Resource
    ISSN: 0305-1846 , 1365-2990
    URL: Issue
    URL: Article
    DOI: 10.1111/nan.2019.45.issue-3
    DOI: 10.1111/nan.12491
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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  • 10
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    Online Resource
    Members of the microRNA-106a-363 Cluster Associate with Unfavorable Outcome in Adult Acute Myeloid Leukemia Patients and Promote Leukemogenesis invivo through Increased Metabolic Activity
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3924-3924
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3924-3924
    Abstract: The miR-106a-363 cluster, encoding six miRNAs (miR-106a, miR-18b, miR-20b, miR-19b, miR-92a and miR-363), is a paralogue of the oncogenic miR-17-92a polycistron and its role in leukemia is at present largely unknown. We aimed to investigate the putative oncogenic role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML) and to dissect the contributions of its individual members to disease formation and progression. First, we analyzed the expression of each miRNA in AML patient samples as well as their clinical relevance. To determine the association of the miR-106a-363 cluster in AML with active disease, we quantified all six miRNAs individually in AML patient samples at initial diagnosis (n=33) and in AML patients in complete remission after chemotherapy (n=6). Hereof, miR-106a-5p, miR-19b-3p and miR-92a-3p levels were significantly lower in remission samples (p=0.0015, p=0.0013 and p=0.0004, respectively), confirming that these miRNAs are upregulated in AML. Stratifying AML patients within the LAML miRNA-Seq dataset of The Cancer Genome Atlas (TCGA) Research Network (n=187) (Ley et al., NEJM, 2013) according to their cytogenetic risk group demonstrated that all members of the cluster, except for miR-18b-5p, significantly associated with adverse cytogenetics. In addition, with the exception of miR-18b-5p, all members associated with an inferior overall survival (OS) in AML patients within the TCGA-LAML dataset, further supporting a pro-leukemogenic role for the cluster. Of note, miR-106a-5p was the most abundantly expressed unique miRNA of the polycistron, both in the TCGA patient cohort and in 11 myeloid leukemia cell lines quantified by quantitative real-time PCR (qRT-PCR). Since the miR-106a-363 cluster is associated with high risk AML, we hypothesized that increased levels of the entire cluster as well as individual members would significantly shorten the survival time in a murine transplantation model mimicking aggressive AML. Therefore, we engineered transplantable, primary murine AML cell lines based on retroviral overexpression of Hoxa9 and Meis1 exhibiting a median disease latency of 39 days (n=14) after syngeneic transplantation in mice. Enforced lentiviral expression of miR-106a-363 (n=13, p 〈 0.0001), miR-106a (n=15, p=0.0003), miR-18b (n=8, p 〈 0.0001), miR-20b (n=13, p 〈 0.0001) and miR-363 (n=13, p 〈 0.0001) in Hoxa9/Meis1 cells significantly accelerated leukemogenesis compared to the control arm. The most pronounced anemia (p=0.03) and the most immature phenotype, based on a significantly higher proportion of c-kit+ (p=0.0147) and a concurrent lower percentage of Mac-1+ and Gr-1+ (p=0.0051) cells, were observed in mice transplanted with Hoxa9/Meis1/miR-106a cells. Based on these results, we focused on the mechanism by which miR-106a contributed to the pathogenesis of AML and performed a proteomics screen comparing Hoxa9/Meis1/miR-106a and Hoxa9/Meis1/control cells. In particular, mitochondrial respiration processes, such as oxidative phosphorylation and electron transport chain components were induced by miR-106a as shown by Gene Set Enrichment Analysis. Preliminary results using high-resolution respirometry further indicated an increased number of mitochondria in Hoxa9/Meis1/miR-106a cells, supporting these findings. In conclusion, we highlight the previously unrecognized oncogenic contribution of the miR-106a-363 polycistron in adult AML. Functional dissection of this cluster, in particular miR-106a, revealed a new therapeutic angle for high risk AML. Disclosures Döhner: Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116035
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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