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    Germline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice

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    Author
    Chappaz, S; Law, CW; Dowling, MR; Carey, KT; Lane, RM; Ngo, LH; Wickramasinghe, VO; Smyth, GK; Ritchie, ME; Kile, BT
    Date
    2020-04-14
    Source Title
    Blood Advances
    Publisher
    AMER SOC HEMATOLOGY
    University of Melbourne Author/s
    Dowling, Mark; Law, Charity; Wickramasinghe, Vihandha; Ritchie, Matthew; Chappaz, Stephanie; Smyth, Gordon; Carey, Kirstyn
    Affiliation
    Medical Biology (W.E.H.I.)
    School of Mathematics and Statistics
    Biochemistry and Molecular Biology
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Chappaz, S., Law, C. W., Dowling, M. R., Carey, K. T., Lane, R. M., Ngo, L. H., Wickramasinghe, V. O., Smyth, G. K., Ritchie, M. E. & Kile, B. T. (2020). Germline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice. BLOOD ADVANCES, 4 (7), pp.1270-1283. https://doi.org/10.1182/bloodadvances.2019001323.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254189
    DOI
    10.1182/bloodadvances.2019001323
    Open Access URL
    http://doi.org/10.1182/bloodadvances.2019001323
    Abstract
    In eukaryotic cells, messenger RNA (mRNA) molecules are exported from the nucleus to the cytoplasm, where they are translated. The highly conserved protein nuclear RNA export factor1 (Nxf1) is an important mediator of this process. Although studies in yeast and in human cell lines have shed light on the biochemical mechanisms of Nxf1 function, its contribution to mammalian physiology is less clear. Several groups have identified recurrent NXF1 mutations in chronic lymphocytic leukemia (CLL), placing it alongside several RNA-metabolism factors (including SF3B1, XPO, RPS15) whose dysregulation is thought to contribute to CLL pathogenesis. We report here an allelic series of germline point mutations in murine Nxf1. Mice heterozygous for these loss-of-function Nxf1 mutations exhibit thrombocytopenia and lymphopenia, together with milder hematological defects. This is primarily caused by cell-intrinsic defects in the survival of platelets and peripheral lymphocytes, which are sensitized to intrinsic apoptosis. In contrast, Nxf1 mutations have almost no effect on red blood cell homeostasis. Comparative transcriptome analysis of platelets, lymphocytes, and erythrocytes from Nxf1-mutant mice shows that, in response to impaired Nxf1 function, the cytoplasmic representation of transcripts encoding regulators of RNA metabolism is altered in a unique, lineage-specific way. Thus, blood cell lineages exhibit differential requirements for Nxf1-mediated global mRNA export.

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