Delineating Human B Cell Precursor Development With Genetically Identified PID Cases as a Model

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints

Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations

Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Flu

Size and Shape Constraints of (486958) Arrokoth from Stellar Occultations

We present the results from four stellar occultations by (486958) Arrokoth, the flyby target of the New Horizons extended mission. Three of the four efforts led to positive detections of the body, and all constrained the presence of rings and other debris, finding none. Twenty-five mobile stations were deployed for 2017 June 3 and augmented by fixed telescopes. There were no positive detections from this effort. The event on 2017 July 10 was observed by the Stratospheric Observatory for Infrared Astronomy with one very short chord. Twenty-four deployed stations on 2017 July 17 resulted in five chords that clearly showed a complicated shape consistent with a contact binary with rough dimensions of 20 by 30 km for the overall outline. A visible albedo of 10% was derived from these data. Twenty-two systems were deployed for the fourth event on 2018 August 4 and resulted in two chords. The combination of the occultation data and the flyby results provides a significant refinement of the rotation period, now estimated to be 15.9380 ± 0.0005 hr. The occultation data also provided high-precision astrometric constraints on the position of the object that were crucial for supporting the navigation for the New Horizons flyby. This work demonstrates an effective method for obtaining detailed size and shape information and probing for rings and dust on distant Kuiper Belt objects as well as being an important source of positional data that can aid in spacecraft navigation that is particularly useful for small and distant bodies.Fil: Buie, Marc W.. Southwest Research Institute.; Estados UnidosFil: Porter, Simon B.. Southwest Research Institute.; Estados UnidosFil: Tamblyn, Peter. Southwest Research Institute.; Estados UnidosFil: Terrell, Dirk. Southwest Research Institute.; Estados UnidosFil: Parker, Alex Harrison. Southwest Research Institute.; Estados UnidosFil: Baratoux, David. Géosciences Environnement Toulouse; Francia. Centre National de la Recherche Scientifique; FranciaFil: Kaire, Maram. Ministry of Higher Education Research and Innovation; Senegal. Asociación Senegalesa para la Promoción de la Astronomía; SenegalFil: Leiva, Rodrigo. Southwest Research Institute.; Estados UnidosFil: Verbiscer, Anne J.. University of Virginia; Estados UnidosFil: Zangari, Amanda M.. Southwest Research Institute.; Estados UnidosFil: Colas, François. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Sorbonne University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Diop, Baidy Demba. Direction de la Formation et de la Communication; SenegalFil: Samaniego, Joseph I.. University of Colorado; Estados UnidosFil: Wasserman, Lawrence H.. Lowell Observatory; Estados UnidosFil: Benecchi, Susan D.. Planetary Science Institute; Estados UnidosFil: Caspi, Amir. Southwest Research Institute.; Estados UnidosFil: Gwyn, Stephen. Herzberg Astronomy and Astrophysics Research Centre; CanadáFil: Kavelaars, J. J.. Herzberg Astronomy and Astrophysics Research Centre; CanadáFil: Ocampo Uría, Adriana C.. National Aeronautics and Space Administration; Estados UnidosFil: Rabassa, Jorge Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Skrutskie, M. F.. University of Virginia; Estados UnidosFil: Soto, Alejandro. Southwest Research Institute.; Estados UnidosFil: Tanga, Paolo. Université Côte d’Azur; Francia. Centre National de la Recherche Scientifique; FranciaFil: Young, Eliot F.. Southwest Research Institute.; Estados UnidosFil: Stern, S. Alan. Southwest Research Institute.; Estados UnidosFil: Andersen, Bridget C.. University of Virginia; Estados UnidosFil: Arango Pérez, Mauricio E.. Universidad de Antioquia; ColombiaFil: Arredondo, Anicia. Massachusetts Institute of Technology; Estados UnidosFil: Artola, Rodolfo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; ArgentinaFil: García Migani, Esteban Andrés. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Geofísica y Astronomía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentin

Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value

Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been described in various types of myeloid malignancies, including acute myeloid leukemia. Analysis of novel markers, such as ASXL1 mutations, in independent clinical trials is indispensable before considering them for clinical decision-making. We analyzed 882 well-characterized acute myeloid leukemia cases to determine the prevalence and prognostic impact of ASXL1 exon12 mutations. Truncating ASXL1 mutations were present in 46 cases (5.3%). ASXL1 mutations were inversely associated with FLT3 internal tandem duplications and mutually exclusive with NPM1 mutations. ASXL1 mutations were an unfavorable prognostic factor as regards survival (median overall survival 15.9 months vs. 22.3 months; P=0.019), with a significantly lower complete response rate (61% vs. 79.6%; P=0.004). In multivariate analyses, ASXL1 mutations were independently associated with inferior poor overall survival (HR 1.52, P=0.032). In conclusion, ASXL1 mutations are common mutations in acute myeloid leukemia and indicate a poor therapy outcome