Association of ASXL1 and RUNX1 Variants with Splenomegaly in Myelodysplastic Syndromes Based on Next-generation Sequencing and Computed Tomography Data: A Retrospective Study

Abstract

Although splenomegaly is typically uncommon in myelodysplastic syndromes (MDS), it is associated with reduced engraftment rates and poor survival outcomes. Despite its clini- cal significance, the incidence and genetic associations of splenomegaly in MDS remain understudied. To address this, we conducted a retrospective study of 27 patients with MDS at the Veterans Health Service Medical Center in South Korea. Based on computed tomography scan evaluation, splenomegaly was identified in 26% of patients with MDS, and significant associations with variants in ASXL1 (P =0.0089 for null and missense/in- frame variants) and RUNX1 (P =0.042 for null variants) were observed, suggesting that these variants are linked to an increased risk of splenomegaly. Notably, one patient with ASXL1 and TET2 variants developed severe splenomegaly (spleen size, 29 cm) following granulocyte colony-stimulating factor (G-CSF) treatment, requiring splenectomy. This case suggests a potential interaction between specific genetic variants and G-CSF sensitivity, potentially exacerbating splenomegaly. Our findings suggest that the incidence of spleno- megaly in patients with MDS, including mild cases, is likely underestimated and that ASXL1 and RUNX1 variants increase the risk of splenomegaly. Furthermore, careful moni- toring for the development of severe splenomegaly during G-CSF treatment may be war- ranted in genetically susceptible individuals with MDS.