ABSTRACT
PURPOSE: To evaluate frequency, biologic features, and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (age 18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n = 269), microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 (5.6%) of 945 cases, predominantly in exons 3 (n = 11), 4 (n = 10), and 8 (n = 23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46 of 640, 7.2%; cytogenetically normal, 34 of 538, 6.3%), whereas they were less frequent in adverse-risk cytogenetics (five of 109, 4.6%) and absent in core-binding-factor AML (0 of 77) and acute promyelocytic leukemia (0 of 61). RUNX1 mutations were associated with MLL-partial tandem duplications (P = .0007) and IDH1/IDH2 mutations (P = .03), inversely correlated with NPM1 (P < .0001), and in trend with CEBPA (P = .10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3), or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, P = .047, for RUNX1-mutated and wild-type patients, respectively), as well as inferior event-free survival (EFS; P < .0001), relapse-free survival (RFS, P = .022), and overall survival (P = .051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (P = .007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem-cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (P < .0001). CONCLUSION: AML with RUNX1 mutations are characterized by distinct genetic properties and are associated with resistance to therapy and inferior outcome.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Adolescent , Adult , Austria , CCAAT-Enhancer-Binding Proteins/genetics , Cytogenetic Analysis , DNA Mutational Analysis , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Exons , Female , Gene Duplication , Gene Expression Profiling/methods , Genotype , Germany , Histone-Lysine N-Methyltransferase , Humans , Isocitrate Dehydrogenase/genetics , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Myeloid-Lymphoid Leukemia Protein/genetics , Nuclear Proteins/genetics , Nucleophosmin , Oligonucleotide Array Sequence Analysis , Phenotype , Prospective Studies , Risk Assessment , Risk Factors , Survival Rate , Tandem Repeat Sequences , Time Factors , Young AdultABSTRACT
Plasmacytoid dendritic cells (PDC) are the main type I interferon (IFN-I) producers and play a central role in innate and adaptive immunity. CD303 (BDCA-2) is a type II c-type lectin specifically expressed by human PDC. CD303 signaling induces tyrosine phosphorylation and Src kinase dependent calcium influx. Cross-linking CD303 results in the inhibition of IFN-I production in stimulated PDC. Here, we demonstrate that PDC express a signalosome similar to the BCR signalosome, consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLCgamma2. CD303 associates with the signaling adapter FcR gamma-chain. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLCgamma2 and cytoskeletal proteins. Analogous to BCR signaling, CD303 signaling is likely linked with its internalization by clathrin-mediated endocytosis. Furthermore, CD303 signaling leads to reduced levels of transcripts for IFN-I genes and IFN-I-responsive genes, indicating that the inhibition of IFN-I production by stimulated PDC is at least partially regulated at the transcriptional level. These results support a possible therapeutic value of an anti-CD303 mAb strategy, since the production of IFN-I by PDC is considered to be a major pathophysiological factor in systemic lupus erythematosus patients.
Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Dendritic Cells/metabolism , Interferon Type I/biosynthesis , Intracellular Signaling Peptides and Proteins/physiology , Lectins, C-Type/physiology , Membrane Glycoproteins/physiology , Multienzyme Complexes/physiology , Phospholipase C gamma/physiology , Protein-Tyrosine Kinases/physiology , Receptors, Immunologic/physiology , Signal Transduction/physiology , Agammaglobulinaemia Tyrosine Kinase , Amino Acid Sequence , Calcium Signaling/physiology , Cells, Cultured/metabolism , CpG Islands , Gene Expression Regulation/physiology , Humans , I-kappa B Proteins/metabolism , Interferon Type I/genetics , Molecular Sequence Data , NF-KappaB Inhibitor alpha , Phosphorylation , Protein Processing, Post-Translational , Receptors, IgG/physiology , Syk Kinase , src-Family Kinases/physiologyABSTRACT
BACKGROUND: Continuous arterial spin labeling (CASL) is a non-invasive technique for the measurement of cerebral blood flow (CBF). The aim of the present study was to examine the reproducibility of CASL measurements and its suitability to consistently detect differences between groups, regions, and resting states. MATERIALS AND METHODS: Thirty-eight healthy subjects (19 female) were examined at 1.5 T on two measurement occasions that were seven weeks apart. Resting CBF was measured with eyes open and eyes closed. RESULTS: In different regions of interest (ROIs) the repeatability estimates varied between 9 and 19 ml/100 g/min. There were no significant mean differences between occasions in all ROIs (P > 0.05). Greater CBF in the eyes-open than in the eyes-closed state was consistently present in the primary and secondary visual areas. Furthermore, CBF was consistently greater in the right than in the left hemisphere (P < 0.05) and differed between lobes and between arterial territories (P < 0.001). Finally, we consistently observed greater CBF in women than in men (P < 0.001). CONCLUSION: This study demonstrates the suitability of CASL to consistently detect differences between groups, regions, and resting states even after seven weeks. This emphasizes its usefulness for longitudinal designs.
Subject(s)
Algorithms , Blood Flow Velocity/physiology , Brain/physiology , Cerebrovascular Circulation/physiology , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Adult , Brain/anatomy & histology , Brain/blood supply , Cerebral Arteries/physiology , Female , Humans , Male , Perfusion/methods , Reproducibility of Results , Sensitivity and Specificity , Spin LabelsABSTRACT
We have recently described a panel of monoclonal antibodies (mAb), that recognize two novel leukocyte surface antigens, BDCA-2 and BDCA-4. BDCA-2 is a novel type II C-type lectin specifically expressed by plasmacytoid dendritic cells (PDCs) that can internalize antigen for presentation to T cells. Furthermore, signaling via BDCA-2 may play a role in switching from interferon (IFN)-alpha/beta-controlled to interleukin (IL)-12-controlled immune response pathways, as triggering of BDCA-2 potently inhibits secretion of IFN-alpha/beta by PDCs and thereby promotes IL-12 p70 production in PDCs and other cells. Viruses may exploit this switch to escape innate antiviral immunity, but it may be beneficial for patients with systemic lupus erythematosus (SLE) if induced, for instance by anti BDCA-2 mAb treatment. BDCA-4 is shown here to be identical to neuropilin-1 (NP-1), a neuronal receptor for the axon guidance factors belonging to the class-3 semaphorin subfamily, and a receptor on endothelial and tumor cells for vascular endothelial growth factor (VEGF-A). In blood and bone marrow, BDCA-4/NP-1 is exclusively expressed on PDCs, but in tonsils also on a few other cells, primarily follicular B helper memory T cells (T(FH)).
