Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Sep 14

PMID 27622333

Citations 220

Authors

Esther A Obeng

Ryan J Chappell

Michael Seiler

Michelle C Chen

Dean R Campagna

Paul J Schmidt

Rebekka K Schneider

Allegra M Lord

Lili Wang

Rutendo G Gambe

Marie E McConkey

Abdullah M Ali

Azra Raza

Lihua Yu

Silvia Buonamici

Peter G Smith

Ann Mullally

Catherine J Wu

Mark D Fleming

Benjamin L Ebert

Affiliations

Soon will be listed here.

Abstract

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.

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