Abstract Number: OC 74.2
Meeting: ISTH 2021 Congress
Background: Schlafen 14 (SLFN14) has recently been identified as an endoribonuclease responsible for cleaving RNA to regulate and inhibit protein synthesis. Early studies revealed members of the SLFN family are capable of altering lineage commitment during T-cell differentiation by using cell cycle arrest as a means of translational control by RNAse activity. SLFN14 has been previously reported as a novel gene causing an inherited macrothrombocytopenia and bleeding in patients. However, the mechanistic role of this endoribonuclease in haematopoiesis and ultimately cell differentiation remains unknown.
Aims: To uncover potential mechanisms for how SLFN14 and its mutations contribute to macrothrombocytopenia and bleeding in patients.
Methods: We generated a CRISPR knock-in mouse model of SLFN14 K208N, homologous to the K219N mutation observed in our previous patient studies. Gross haematological analysis, in vitro and in vivo studies of platelet and erythrocyte function, as well as analysis of spleen and bone marrow progenitors were used to decipher differences in haematopoiesis between CRISPR knock-in and wild-type mice.
Results: Homozygous mice for the K208N mutation do not survive to weaning age due to severe anaemia. Heterozygotes exhibit microcytic erythrocytosis, haemolytic anaemia, splenomegaly and abnormal thrombus formation examined by intravital microscopy although in vitro platelet function and morphology remain unchanged. Differences are observed in erythroid progenitors in the spleens and bone marrow of these mice, indicative of an upregulation of erythropoiesis. RT-PCR of transcription factor GATA1 in SLFN14 K208N mice revealed significant reduction in GATA1 mRNA from whole bone marrow suggestive of SLFN14 endoribonuclease activity in haematopoiesis.
Conclusions: This SLFN14 mutation presents distinct species-specific phenotypes, with a platelet defect reported in humans and a severe microcytic erythrocytosis in mice. Thus concluding that SLFN14 is a key regulator in mammalian haematopoiesis and a species-specific mediator of platelet and erythroid lineage commitment.
To cite this abstract in AMA style:Stapley R, Smith C, Haining E, Bacon A, Lax S, Pisareva V, Pisarev A, Watson S, Khan A, Morgan N. A Heterozygous Mutation in SLFN14 Influences Species-specific Haematopoietic Regulation in Platelet and Erythroid Lineages [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-heterozygous-mutation-in-slfn14-influences-species-specific-haematopoietic-regulation-in-platelet-and-erythroid-lineages/. Accessed March 4, 2024.
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