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Ref Type Journal Article
PMID (36746437)
Authors Jing CB, Prutsch N, He S, Zimmerman MW, Landesman Y, Look AT
Title Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors.
Journal Vol Issue Date Pages Journal Short Title
British journal of haematology 2023 Feb 06 489-501 Br J Haematol
URL
Abstract Text TET2 inactivating mutations serve as initiating genetic lesions in the transformation of haematopoietic stem and progenitor cells (HSPCs). In this study, we analysed known drugs in zebrafish embryos for their ability to selectively kill tet2-mutant HSPCs in vivo. We found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill tet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murine Tet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and also TET2-inactivated human acute myeloid leukaemia (AML) cells. Selective killing of TET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding that TET2 loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of the selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of TET2-mutant haematopoietic malignancies, and to suppress clonal expansion in age-related TET2-mutant clonal haematopoiesis.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
TET2 del acute myeloid leukemia sensitive Selinexor Preclinical - Cell culture Actionable In a preclinical study, Xpovio (selinexor) induced apoptosis in TET2-knockout acute myeloid leukemia cell lines, resulting in decreased cell viability in culture (PMID: 36746437). 36746437
TET2 del acute myeloid leukemia sensitive KPT-8602 Preclinical - Cell culture Actionable In a preclinical study, Eltanexor (KPT-8602) induced apoptosis in TET2-knockout acute myeloid leukemia cell lines, resulting in decreased cell viability in culture (PMID: 36746437). 36746437