title: Splicing factor 3b subunit 1 (Sf3b1) haploinsufficient mice display features of low risk Myelodysplastic syndromes with ring sideroblasts.
abstract: 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.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. visconv@ccf.org.
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. ali.tabarroki@gmail.com.
authors.forename: Ali
authors.initials: A
authors.lastname: Tabarroki
authors.affiliation: Department of Medicine, University of California, School of Medicine, San Francisco, CA, USA. Li.Zhang@ucsf.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. parkery2@ccf.org.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Parker
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. hasrouni86@gmail.com.
authors.forename: Edy
authors.initials: E
authors.lastname: Hasrouni
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. mahfour@ccf.org.
authors.forename: Reda
authors.initials: R
authors.lastname: Mahfouz
authors.affiliation: Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama Institute, Yokohama, Japan. isono@rcai.riken.jp.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Isono
authors.affiliation: Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama Institute, Yokohama, Japan. koseki@rcai.riken.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. sekerem@ccf.org.|Leukemia Program, Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. sekerem@ccf.org.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. saunthy@ccf.org.|Leukemia Program, Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. saunthy@ccf.org.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA. barnarj@ccf.org.
authors.forename: John
authors.initials: J
authors.lastname: Barnard
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. lindned@ccf.org.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindner
authors.affiliation: Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA. rogersj5@ccf.org.
authors.forename: Heesun J
authors.initials: HJ
authors.lastname: Rogers
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH, USA, 44195. ramontiumd@gmail.com.|Leukemia Program, Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. ramontiumd@gmail.com.
authors.forename: Ramon V
authors.initials: RV
authors.lastname: Tiu
mesh_terms: D000756:Anemia, Sideroblastic / Q000097:blood / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000097:blood / Q000235:genetics*; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000097:blood / Q000235:genetics*; D012307:Risk Factors
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C491799:Sf3b1 protein, mouse