PUBLICATION
Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors
- Authors
- Jing, C.B., Prutsch, N., He, S., Zimmerman, M.W., Landesman, Y., Look, A.T.
- ID
- ZDB-PUB-230207-26
- Date
- 2023
- Source
- British journal of haematology 201(3): 489-501 (Journal)
- Registered Authors
- He, Shuning, Jing, Chang-Bin, Look, A. Thomas, Zimmerman, Mark
- Keywords
- HSPC, TET2, XPO1, clonal haematopoiesis, eltanexor, selinexor
- MeSH Terms
-
- Animals
- DNA-Binding Proteins/genetics
- Dioxygenases*/metabolism
- Hematopoietic Stem Cells/metabolism
- Humans
- Leukemia, Myeloid, Acute*/drug therapy
- Leukemia, Myeloid, Acute*/genetics
- Leukemia, Myeloid, Acute*/pathology
- Mice
- Zebrafish
- PubMed
- 36746437 Full text @ Br. J. Haematol.
Citation
Jing, C.B., Prutsch, N., He, S., Zimmerman, M.W., Landesman, Y., Look, A.T. (2023) Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors. British journal of haematology. 201(3):489-501.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping