Splicing factor 3b subunit 1 (Sf3b1) haploinsufficient mice display features of low risk 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.