Synthetic lethal targeting of TET2‐mutant haematopoietic stem and progenitor cells by XPO1 inhibitors

Summary 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...

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Bibliographic Details
Published in:British journal of haematology 2023-05, Vol.201 (3), p.489-501
Main Authors: Jing, Chang‐Bin, Prutsch, Nicole, He, Shuning, Zimmerman, Mark W., Landesman, Yosef, Look, A. Thomas
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Animals
Apoptosis
Ataxin
Cell death
clonal haematopoiesis
Dioxygenases - metabolism
DNA damage
DNA-Binding Proteins - genetics
eltanexor
Embryos
Exportin 1 Protein
Genetic transformation
Hematology
Hematopoietic Stem Cells - metabolism
Hemopoiesis
HSPC
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Malignancy
Mice
Mutants
Progenitor cells
selinexor
TET2
XPO1
Zebrafish
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Summary:Summary 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.
ISSN:0007-1048
1365-2141
DOI:10.1111/bjh.18667