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Ref Type Journal Article
PMID (27622333)
Authors Obeng EA, Chappell RJ, Seiler M, Chen MC, Campagna DR, Schmidt PJ, Schneider RK, Lord AM, Wang L, Gambe RG, McConkey ME, Ali AM, Raza A, Yu L, Buonamici S, Smith PG, Mullally A, Wu CJ, Fleming MD, Ebert BL
Title Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.
Journal Cancer cell
Vol 30
Issue 3
Date 2016 Sep 12
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
E7107 E7107 10 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
E7107 E7107 is a derivative of Pladienolide D, which inhibits assembly of the spliceosome specifically by binding to SF3B1, thereby inhibiting splicing of pre-mRNA and cell-cycle progression (PMID: 27622333).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SF3B1 K700E hematologic cancer sensitive E7107 Preclinical - Cell culture Actionable In a preclinical study, mouse cells expressing SF3B1 K700E demonstrated sensitivity to E7107 in culture, resulting in decreased viability of cells (PMID: 27622333). 27622333