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

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.

The Nuclear Pore Complex and mRNA Export in Cancer

“…The RNA export factor ALY is elevated in oral squamous cell carcinoma patient specimens [ 112 ]. Recent studies indicate that mutation of NXF1 in mice can lead to disruptions in hematopoiesis in a lineage-specific manner [ 113 ], and NXF1 has been found to be mutated in chronic lymphocytic leukemia (CLL) patients [ 114 , 115 , 116 ]. The germinal center associated protein (GANP), a component of the TREX2 complex, is highly elevated in several types of lymphomas [ 117 ].…”

Polyadenylate-binding protein cytoplasmic 1 mediates alternative splicing events of immune-related genes in gastric cancer cells

“…55 In mice, RNA metabolism is disturbed by heterozygous mutations of NXF1 , which induces lymphopenia. 56 Moreover, GTF3C1 is required for RNA polymerase III-mediated transcription, and its prognostic significance has been reported in colorectal cancer. 57 Furthermore, PABPC1 may influence the development of GC by regulating AS events, affecting gene expression and protein function, which in turn changes the expression signature of downstream genes.…”

Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

“…The highly conserved protein nuclear RNA export factor 1 (Nxf1) is an important mediator of mRNA export from the nucleus to the cytoplasm [ 28 ]. Based on two “omics” approaches, NXF1 was identified as one of the IRF5 signaling pathway regulators, and in turn genome-wide association studies have implied the association of IRF5 with several autoimmune diseases, including SLE, Sjogren’s syndrome, inflammatory bowel disease, and MS [ 29 ].…”