Myelodysplastic syndromes with ring sideroblasts

Background: The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1) mice which are rarely found in mouse models of MDS. Sf3b1 mice were originally engineered to study the interaction between polycomb genes and other proteins. Methods: We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 and Sf3b1 mice. We then performed a comprehensive RNA-sequencing analysis to evaluate the transcriptome of BM cells from Sf3b1 and Sf3b1 mice. Results: Sf3b1 exhibited macrocytic anemia (MCV: 49.5 ± 1.6 vs 47.2 ± 1.4; Hgb: 5.5 ± 1.7 vs 7.2 ± 1.0) and thrombocytosis (PLTs: 911.4 ± 212.1 vs 878.4 ± 240.9) compared to Sf3b1 mice. BM analysis showed dyserythropoiesis and occasional RS in Sf3b1 mice. The splenic architecture showed increased megakaryocytes with hyperchromatic nuclei, and evidence of extramedullary hematopoiesis. RNA-sequencing showed higher expression of a gene set containing Jak2 in Sf3b1 compared to Sf3b1. Conclusions: Our study indicates that Sf3b1 mice manifest features of low risk MDS-RS and may be relevant for preclinical therapeutic studies.