9 results on '"Sabrina Inselmann"'
Search Results
2. Cloning and characterization of a novel druggable fusion kinase in acute myeloid leukemia
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Sonja K. Hühn, Lutz B. Jehn, Gert Bange, Christian Michel, Ying Wang, André Marquardt, Clara Simon, Elisabeth Mack, Christopher-Nils Mais, Lea V. Fritz, Andreas Neubauer, Andreas Burchert, Ellen Wollmer, Jennifer Kremer, Kristina Sohlbach, Cornelia Brendel, Claudia Haferlach, and Sabrina Inselmann
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Cloning ,Leukemia, Myeloid, Acute ,Oncogene Proteins, Fusion ,Kinase ,Druggability ,Humans ,Myeloid leukemia ,Hematology ,Computational biology ,Cloning, Molecular ,Biology ,Online Only Articles - Published
- 2019
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3. PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation
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Christoph Schliemann, Andreas Neubauer, Sabrina Inselmann, Bianca Altvater, We Berdel, Kristina Sohlbach, Andreas Burchert, M Lohoff, Tim Sauer, Wolfgang Hartmann, J R Knorrenschild, Jörn C. Albring, Sareetha Kailayangiri, M Stelljes, Christoph Groth, and Claudia Rossig
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Adult ,Male ,0301 basic medicine ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,medicine ,Humans ,Progenitor cell ,neoplasms ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Allografts ,medicine.disease ,Blockade ,Leukemia, Myeloid, Acute ,Leukemia ,Nivolumab ,surgical procedures, operative ,030104 developmental biology ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Female ,biological phenomena, cell phenomena, and immunity ,Stem cell ,business - Abstract
PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation
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- 2016
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4. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML
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E. Eigendorff, Christian Dietz, Cornelius F. Waller, G. Freunek, Martin C. Müller, Thomas Illmer, Mahon Fx, Andreas Neubauer, Florian Finkernagel, T H Brümmendorf, Joelle Guilhot, Stefan Hanzel, Rüdiger Hehlmann, Cornelia Brendel, Sabrina Inselmann, Magdalena Huber, S K Metzelder, Jolanta Dengler, Andreas Burchert, Yanfeng Wang, Susanne Saussele, Markus Pfirrmann, Thoralf Lange, Mariele Goebeler, Regina Herbst, Andreas Hochhaus, and Christin Schütz
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Cancer Research ,medicine.drug_class ,Gene Expression ,Cell Count ,Kaplan-Meier Estimate ,Tyrosine-kinase inhibitor ,Immunophenotyping ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Recurrence ,T-Lymphocyte Subsets ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,CTLA-4 Antigen ,Protein Kinase Inhibitors ,Aged ,Hematology ,business.industry ,Remission Induction ,Myeloid leukemia ,hemic and immune systems ,Dendritic Cells ,Middle Aged ,medicine.disease ,Prognosis ,Lymphoma ,Discontinuation ,Leukemia ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Female ,B7-2 Antigen ,business ,CD8 ,Biomarkers - Abstract
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P 95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with 8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.
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- 2018
5. Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia
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J Hoffmann, Sabrina Inselmann, Andreas Hochhaus, Philippe Kostrewa, Ruediger Hehlmann, Kristina Sohlbach, E. Eigendorff, Martin C. Müller, Andreas Neubauer, Andreas Burchert, J Ziermann, S K Metzelder, C. Schütz, and Susanne Saussele
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Alpha interferon ,Antineoplastic Agents ,Interferon alpha-2 ,Piperazines ,Cohort Studies ,Young Adult ,Maintenance therapy ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Neoplasm Staging ,Hematology ,business.industry ,Remission Induction ,Interferon-alpha ,Myeloid leukemia ,Imatinib ,Middle Aged ,Prognosis ,medicine.disease ,Recombinant Proteins ,Discontinuation ,Lymphoma ,Survival Rate ,Leukemia ,Pyrimidines ,Benzamides ,Immunology ,Imatinib Mesylate ,Drug Therapy, Combination ,Female ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,medicine.drug - Abstract
A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.
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- 2015
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6. NFATc1 as a therapeutic target in FLT3-ITD-positive AML
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Thorsten Stiewe, Andreas Neubauer, S Gattenlöhner, S K Metzelder, Kristina Sohlbach, Martin Bornhäuser, Sabrina Inselmann, Andreas Burchert, Elisabeth Hessmann, Joël P. Charles, M Solovey, Christian Michel, Ying Wang, M von Bonin, M Rehberger, A Ten Haaf, Volker Ellenrieder, and Cornelia Brendel
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Cancer Research ,Myeloid ,Apoptosis ,Pharmacology ,Small hairpin RNA ,Immunoenzyme Techniques ,fluids and secretions ,0302 clinical medicine ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,RNA, Small Interfering ,Oligonucleotide Array Sequence Analysis ,0303 health sciences ,Hematology ,Reverse Transcriptase Polymerase Chain Reaction ,Myeloid leukemia ,hemic and immune systems ,NFAT ,Sorafenib ,Flow Cytometry ,Prognosis ,3. Good health ,Survival Rate ,Leukemia ,Haematopoiesis ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Tandem Repeat Sequences ,030220 oncology & carcinogenesis ,embryonic structures ,Cyclosporine ,Immunosuppressive Agents ,medicine.drug ,Niacinamide ,medicine.medical_specialty ,Blotting, Western ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,RNA, Messenger ,neoplasms ,Protein Kinase Inhibitors ,030304 developmental biology ,Cell Proliferation ,Neoplasm Staging ,NFATC Transcription Factors ,business.industry ,Gene Expression Profiling ,Phenylurea Compounds ,medicine.disease ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Mutation ,Neoplasm Recurrence, Local ,business - Abstract
Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.
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- 2015
7. Bacterial natural transformation by highly fragmented and damaged DNA
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Pål Jarle Johnsen, Anthony M. Poole, Eske Willerslev, Søren Brunak, Wilfried Wackernagel, Kaare Magne Nielsen, J. Victor Moreno Mayar, Rasmus Nielsen, Klaus Harms, Ludovic Orlando, Oliver G. Pybus, Thomas Sicheritz-Pontén, Tais W. Dahl, Simon Rasmussen, Sabrina Inselmann, Johann de Vries, Søren Overballe-Petersen, and Minik T. Rosing
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Woolly mammoth ,Gene Transfer, Horizontal ,DNA damage ,Molecular Sequence Data ,Genome ,Natural (archaeology) ,Evolution, Molecular ,chemistry.chemical_compound ,Mammoths ,Animals ,DNA Primers ,Genetics ,Multidisciplinary ,biology ,Acinetobacter ,Base Sequence ,fungi ,DNA ,Sequence Analysis, DNA ,Biological Sciences ,biology.organism_classification ,Transformation (genetics) ,chemistry ,Horizontal gene transfer ,Transformation, Bacterial ,Bacteria ,DNA Damage - Abstract
DNA molecules are continuously released through decomposition of organic matter and are ubiquitous in most environments. Such DNA becomes fragmented and damaged (often100 bp) and may persist in the environment for more than half a million years. Fragmented DNA is recognized as nutrient source for microbes, but not as potential substrate for bacterial evolution. Here, we show that fragmented DNA molecules (≥ 20 bp) that additionally may contain abasic sites, cross-links, or miscoding lesions are acquired by the environmental bacterium Acinetobacter baylyi through natural transformation. With uptake of DNA from a 43,000-y-old woolly mammoth bone, we further demonstrate that such natural transformation events include ancient DNA molecules. We find that the DNA recombination is RecA recombinase independent and is directly linked to DNA replication. We show that the adjacent nucleotide variations generated by uptake of short DNA fragments escape mismatch repair. Moreover, double-nucleotide polymorphisms appear more common among genomes of transformable than nontransformable bacteria. Our findings reveal that short and damaged, including truly ancient, DNA molecules, which are present in large quantities in the environment, can be acquired by bacteria through natural transformation. Our findings open for the possibility that natural genetic exchange can occur with DNA up to several hundreds of thousands years old.
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- 2013
8. Frequency of CTLA-4 Receptor Ligand (CD86, B7.2) -Positive Plasmacytoid Dendritic Cells Predicts Risk of Disease Recurrence after Tyrosine-Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Results from a Prospective Substudy of the Euroski Trial
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Jolanta Dengler, Martin C. Müller, Susanne Saussele, Thoralf Lange, Stefan Hanzel, Andreas Neubauer, Thomas Illmer, Cornelia Brendel, Sabrina Inselmann, Andreas Hochhaus, Ying Wang, Christin Schütz, Ekkehard Eigendorff, Maria Elisabeth Goebeler, Regina Herbst, Tim H. Brümmendorf, Finkernagel Florian, Christian Dietz, Cornelius F. Waller, François Xavier Mahon, Gernot Freunek, Joelle Guilhot, and Andreas Burchert
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business.industry ,medicine.drug_class ,Lymphocyte ,Immunology ,Myeloid leukemia ,hemic and immune systems ,Ipilimumab ,Cell Biology ,Hematology ,Biochemistry ,Immune checkpoint ,Tyrosine-kinase inhibitor ,Discontinuation ,medicine.anatomical_structure ,CTLA-4 ,Medicine ,Interleukin-3 receptor ,business ,medicine.drug - Abstract
Background Chronic myeloid leukemia (CML) stem cells are inherently insensitive to tyrosine-kinase inhibitors (TKI). However, an important minority of CML patients was shown to discontinue TKI without experiencing molecular relapse. Underlying mechanisms are currently unknown. Plasmacytoid dendritic cells (pDCs) are critical regulators of immune responses. Following activation, pDC upregulate MHC-class II and other DC activation markers such as CD86 (also known as B7.2). CD86 is a co-stimulatory molecule during T-cell activation, but also ligand of the inhibitory immune checkpoint receptor CTLA-4, which counteracts T-cell activation. The origin and function of pDC in CML biology is unknown. Within a sub-study of the EUROSKI TKI discontinuation trial we prospectively tested the hypothesis that pDC counts and CD86 expression status govern relapse risk following TKI discontinuation. Methods: Using flow cytometry, cell sorting and fluorescence in situ hybridization (FISH), CD86 expression and BCR-ABL status were analyzed in PDCA-2+/CD123+ peripheral blood (pB) pDC of untreated CML patients (CML pDC), normal donors and 123 patients, who had stopped TKI therapy in deep molecular remission within the international EUROSKI study (EUDRACT 2011-000440-22). All 123 EUROSKI patients had given written informed consent to participate in the immunological sub-study of the EUROSKI trial. Fresh samples from 19 EUROSKI centers in Germany were centrally analyzed prior, as well as 1, 2, 3 and 6 months after TKI discontinuation. PB CD86+ pDC counts were calculated per 105 cells in the lymphocyte gate. Decision trees and 10-fold cross validation were employed to establish relapse prediction accuracy for this value. Results CML pDC were BCR-ABL-FISH positive (median: 81%; range, 57 to 100%). In contrast, the proportion of CD86+ CML pDC varied substantially (median: 25.9%, range 3.2% to 82.4%), suggesting that CD86 expression on CML pDC was not a direct consequence of oncogenic BCR-ABL signaling. This was confirmed experimentally in a murine CML model. In contrast to CML pDC, remission pDC were always BCR-ABL FISH negative (n=10), but still displayed a comparable high proportion of CD86 positive pDC (median: 21%; range, 2.2% to 62%). In contrast, normal donor pDC were rarely CD86 positive (median: 6.8%; range, 4.2% to 17%), reinforcing the aberrant, and BCR-ABL-independent nature of CD86 expression on CML and remission pDC. As a result, healthy donors displayed only between 26 to 84 CD86+ pDC per 105 lymphocytes, whereas EUROSKI remission patients exhibited between 6 to 309 CD86+ pDC per 105 lymphocytes. Based on the important role of CD86 as a high affinity ligand of the inhibitory immune checkpoint receptor CTLA-4, we next asked, whether CD86+ pDC counts are associated with relapse risk after TKI discontinuation. Strikingly, statistical models suggested that a CD86+ pDC count below or above 95 CD86+ pDC/105 lymphocytes optimally separated two relapse categories of EUROSKI patients. Whereas relapse free survival (RFS) (loss of MMR) for patients with more than 95 CD86+ pDC/105 lymphocytes was 30% (n=32), RFS was 69% for patients (n=91) with less than 95 CD86+ pDC/105 lymphocytes (p Conclusion: Our data suggest for the first time a mechanism that governs relapse biology after TKI discontinuation in CML. It is proposed that a chronic engagement of the T-cell inhibitory immune checkpoint receptor CTLA-4 by abundant levels of CD86+ on remission pDC impedes a T-cell-dependent control of CML stem cell survival after stopping TKI. CTLA-4 blocking antibodies such as ipilimumab might therefore prevent molecular relapse and overcome stem cell persistence in CML especially in patients with high CD86+ pDC counts. Figure 1. Relapse free survival after TKI discontinuation according to the number of CD86+ pDC at the time of stopping TKI in the EURO-SKI trial. Figure 1. Relapse free survival after TKI discontinuation according to the number of CD86+ pDC at the time of stopping TKI in the EURO-SKI trial. Disclosures Burchert: Bristol Myers Squibb: Honoraria. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; ARIAD: Honoraria. Müller:Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Lange:Novartis: Research Funding. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:NOVARTIS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy, Honoraria.
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- 2015
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9. BCR-ABL-Induced Transcriptional Repression of the Interferon Regulatory Factor 8 (IRF-8/ICSBP) Leads to Depletion of Plasmocytoid Dendritic Cells (PDC), Which May Contribute to Leukemogenesis in a Murine Model of Chronic Myeloid Leukemia
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Cornelia Brendel, Andreas Neubauer, Sabrina Inselmann, Simone Liebler, Steffen Koschmieder, and Andreas Burchert
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education.field_of_study ,Adoptive cell transfer ,Immunology ,Population ,Myeloid leukemia ,hemic and immune systems ,macromolecular substances ,Cell Biology ,Hematology ,Dendritic cell ,Biology ,Biochemistry ,Transplantation ,Haematopoiesis ,hemic and lymphatic diseases ,Cancer research ,Progenitor cell ,IRF8 ,education - Abstract
Abstract 36 Introduction: Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. CML patients lack expression of IRF-8 - an interferon-regulated transcription factor that has been shown to exert tumor suppressor functions. IRF-8 is also critical for the development of a rare dendritic cell population, so called plasmocytoid dendritic cells (PDC). PDC are quantitatively significantly reduced or absent in the peripheral blood of first diagnosis CML patients. PDC are also the major producers of IFN-alpha (IFNa) in man. IFNa is a cytokine that has significant therapeutic efficiency in the treatment of CML patients. We here wished to experimentally test, whether BCR-ABL expression and loss of IRF-8 may be causally linked to a reduction of PDC in murine CML and whether there could be any functional relevance for PDC loss in CML development or treatment. Methods: PDC counts were studied from peripheral blood samples of primary CML patients at diagnosis, at the time of remission or from healthy donors. PDC function was assessed in vitro by treatment of magnetic bead-enriched PDC with Toll-like receptor 9-specific oligos (ODN 2216) and subsequent assessment of the intracellular IFNa expression in stimulated PDC. A supposed link between BCR-ABL expression, IRF-8 repression and loss of PDC counts was studied in vivo using a murine CML transduction-transplantation model (C57/Bl6 mice, 7Gy sub-lethal irradiation for conditioning). Multiparameter flow cytometry and cell sorting were performed to analyze and enrich, BCR-ABL-positive (GFP+) hematopoietic subpopulations and PDC in order to then quantitate their IRF-8 and BCR-ABL transcript level by RT-PCR. In order to also test the functional relevance of PDC during CML leukemogenesis, CML mice were injected intravenously, weekly from day +5 after transplantation with in vitro generated PDC. Mice were simultaneously also s.c.-injected weekly with ODN 2216 to stimulate IFNα secretion in adoptively transferred PDC in vivo. Results: As previously reported, newly diagnosed CML patients displayed a significantly reduced PDC count when compared to healthy donors (p CML mice developed a fatal, BCR-ABL-positive myeloproliferation within 13 to 29 days with 88% penetrance. Compared to control mice (n=8), CML mice (n=14) showed a 7-fold and 3-fold reduction of the frequency of B220+mPDCA-1+ PDC in bone marrow and spleen, respectively. This was associated with a statistically significant (4-fold) suppression of IRF8 mRNA expression in sorted BCR-ABL(GFP)-positive PDC relative to BCR-ABL-negative PDC from the same mice (n=3) or from control transplantations (n=5). By RT-PCR, there was a trend also for lower IRF8 expression in CML progenitor cells (Lin− c-Kit+ Sca-1- GFP+), but not in the stem cell enriching population (Lin− c-Kit+ Sca-1+ GFP+). This implied that IRF8 expression is lost during BCR-ABL-induced leukemogenesis in more mature compartments, which supposedly include PDC precursors. Intriguingly, a once weekly adoptive transfer of in vitro generated (to > 30% enriched) PDC for three successive weeks combined with a once weekly subcutaneous injection of CpG ODN 2216 for three weeks was sufficient to almost double survival of CML mice. Conclusions: Using a murine model of CML, we provide first experimental evidence that BCR-ABL induced myeloproliferation is causally linked to a quantitative suppression of PDC, and that this is associated with a BCR-ABL-mediated suppression of IRF8 transcription. Since adoptively transferred PDC were capable of counteracting murine CML development, BCR-ABL may facilitate leukemogenesis in part by obstructing PDC maturation. PDC could thus be a novel immunological effector cell population that exerts and/or integrates anti-leukemic immune responses in CML. Disclosures: No relevant conflicts of interest to declare.
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- 2012
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