Splicing factor 3b subunit 1 (Sf3b1) haploinsufficient mice display features of low risk Myelodysplastic syndromes with ring sideroblasts

Journal of Hematology & Oncology

Ramon V Tiu⁴  Heesun J Rogers⁶  Daniel Lindner²  John Barnard¹  Yogen Saunthararajah⁴  Mikkael A Sekeres⁴  Haruhiko Koseki⁵  Kyoichi Isono⁵  Reda Mahfouz²  Edy Hasrouni²  Yvonne Parker²  Li Zhang³  Ali Tabarroki²  Valeria Visconte² 

[1] Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland 44195OH, USA;Department of Medicine, University of California, School of Medicine, San Francisco, CA, USA;Leukemia Program, Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA;Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama Institute, Yokohama, Japan;Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA

关键词: RNA-sequencing;    Myelodysplasia;    SF3B1 mice;   

Others  :  1137554
DOI  :  10.1186/s13045-014-0089-x

 received in 2014-10-13, accepted in 2014-11-15,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Visconte et al.; licensee BioMed Central Ltd.

【 图 表 】

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