Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1(K700E). Sf3b1(K700E) mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1(K700E) myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1(K700E) to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1(K700E)-expressing cells. Thus, SF3B1(K700E) expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Esther A
EA
Obeng
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ryan J
RJ
Chappell
H3 Biomedicine, Inc., Cambridge, MA 03129, USA.
Michael
M
Seiler
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Michelle C
MC
Chen
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Dean R
DR
Campagna
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Paul J
PJ
Schmidt
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Rebekka K
RK
Schneider
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Allegra M
AM
Lord
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Lili
L
Wang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Rutendo G
RG
Gambe
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Marie E
ME
McConkey
Division of Hematology/Oncology, Columbia University Medical Center, New York, NY 10027, USA.
Abdullah M
AM
Ali
Division of Hematology/Oncology, Columbia University Medical Center, New York, NY 10027, USA.
Azra
A
Raza
H3 Biomedicine, Inc., Cambridge, MA 03129, USA.
Lihua
L
Yu
H3 Biomedicine, Inc., Cambridge, MA 03129, USA.
Silvia
S
Buonamici
H3 Biomedicine, Inc., Cambridge, MA 03129, USA.
Peter G
PG
Smith
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ann
A
Mullally
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Catherine J
CJ
Wu
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Mark D
MD
Fleming
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: bebert@partners.org.
Benjamin L
BL
Ebert
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017381:Spliceosomes / Q000502:physiology*
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; C491799:Sf3b1 protein, mouse; D049308:Dioxygenases; C541081:TET2 protein, human; C551914:Tet2 protein, mouse