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|Ref Type||Journal Article|
|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.|
|Date||2016 Sep 12|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|