Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells by XPO1 inhibitors
TET2 inactivating mutations serve as initiating genetic lesions in the transformation of hematopoietic stem and progenitor cells (HSPCs). In this study, we analyzed known drugs in zebrafish embryos for their abilities to selectively kill tet2 -mutant HSPCs in vivo , and we found that the exportin 1...
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Published in | British journal of haematology Vol. 201; no. 3; pp. 489 - 501 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
06.02.2023
|
Online Access | Get full text |
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Summary: | TET2
inactivating mutations serve as initiating genetic lesions in the transformation of hematopoietic stem and progenitor cells (HSPCs). In this study, we analyzed known drugs in zebrafish embryos for their abilities to selectively kill
tet2
-mutant HSPCs
in vivo
, and 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 leukemia (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 selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of
TET2
-mutant hematopoietic malignancies and to suppress clonal expansion in age-related
TET2
-mutant clonal hematopoiesis. |
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Bibliography: | These authors contributed equally to this manuscript. Authorship contributions: C.-B. J., N.P., Y.L., and A.T.L. designed research; C.-B. J., N.P., performed research; C.-B. J., N.P., M.Z., S.H., Y.L., and A.T.L. analyzed data; and C.-B. J., N.P., M.Z., S.H., Y.L., and A.T.L. wrote the paper. |
ISSN: | 0007-1048 1365-2141 |
DOI: | 10.1111/bjh.18667 |