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dc.contributor.authorChappaz, S
dc.contributor.authorLaw, CW
dc.contributor.authorDowling, MR
dc.contributor.authorCarey, KT
dc.contributor.authorLane, RM
dc.contributor.authorNgo, LH
dc.contributor.authorWickramasinghe, VO
dc.contributor.authorSmyth, GK
dc.contributor.authorRitchie, ME
dc.contributor.authorKile, BT
dc.date.accessioned2020-12-14T06:21:05Z
dc.date.available2020-12-14T06:21:05Z
dc.date.issued2020-04-14
dc.identifierpii: 454186
dc.identifier.citationChappaz, 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.
dc.identifier.issn2473-9529
dc.identifier.urihttp://hdl.handle.net/11343/254189
dc.description.abstractIn 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.
dc.languageEnglish
dc.publisherAMER SOC HEMATOLOGY
dc.titleGermline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice
dc.typeJournal Article
dc.identifier.doi10.1182/bloodadvances.2019001323
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentSchool of Mathematics and Statistics
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titleBlood Advances
melbourne.source.volume4
melbourne.source.issue7
melbourne.source.pages1270-1283
melbourne.elementsid1444471
melbourne.openaccess.urlhttp://doi.org/10.1182/bloodadvances.2019001323
melbourne.openaccess.statusPublished version
melbourne.contributor.authorDowling, Mark
melbourne.contributor.authorLaw, Charity
melbourne.contributor.authorWickramasinghe, Vihandha
melbourne.contributor.authorRitchie, Matthew
melbourne.contributor.authorChappaz, Stephanie
melbourne.contributor.authorSmyth, Gordon
melbourne.contributor.authorCarey, Kirstyn
dc.identifier.eissn2473-9537
melbourne.accessrightsAccess this item via the Open Access location


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