Molecular targets for therapy

Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells (HSPCs) with TOP1-targeted drugs and PARP1 inhibitors

Abstract

Inactivating mutations in TET2 serve as an initiating genetic lesion in the transformation of hematopoietic stem and progenitor cells (HSPCs). Thus, effective therapy for this subset of patients would ideally include drugs that are selectively lethal in TET2-mutant HSPCs, at dosages that spare normal HSPCs. In this study, we tested 129 FDA-approved anticancer drugs in a tet2-deficient zebrafish model and showed that topoisomerase 1 (TOP1)-targeted drugs and PARP1 inhibitors selectively kill tet2-mutant HSPCs. We found that Tet2-deficient murine bone marrow progenitors and CRISPR-Cas9-induced TET2-mutant human AML cells were more sensitive to both classes of drugs compared with matched control cells. The mechanism underlying the selective killing of TET2-mutant blood cells by these drugs was due to aberrantly low levels of tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that is important for removing TOP1 cleavage complexes (TOP1cc). Low TDP1 levels yield sensitivity to TOP1-targeted drugs or PARP1 inhibitors and an inability to remove TOP1 cleavage complexes, leading to DNA double-strand breaks and cell death. The finding that TET2 mutations render HSPCs uniquely vulnerable to disruption of TOP1 and PARP1 activity may therefore represent a unique opportunity to use relatively low dosages of these drugs for the “precision therapy” of TET2-mutant myeloid malignancies.

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Fig. 1: tet2-mutant HSPCs are hypersensitive to topotecan.
Fig. 2: Topotecan treatment induces DNA double-strand breaks and triggers apoptosis in tet2-mutant zebrafish HSPCs.
Fig. 3: A decrease in tdp1 expression confers topotecan hypersensitivity to tet2-mutant HSPCs.
Fig. 4: A decrease in tdp1 expression confers hypersensitivity to PARP1 inhibition in tet2-mutant HSPCs.
Fig. 5: Topotecan selectively kills Tet2-mutant murine progenitor cells and human OCI-AML2 cells.
Fig. 6: Olaparib selectively kills Tet2-mutant murine progenitor cells and human OCI-AML2 cells.

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Acknowledgements

We thank Cicely Jette and John Gilbert for editorial assistance and critical comments. This work was supported by Edward P. Evans Foundation (to ATL); the Andrew McDonough B+ Foundation (to C-BJ), and an International Award of Lady Tata Memorial Trust (to C-BJ).

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C-BJ and CF contributed to experimental work, experimental design, writing, and data analysis and interpretation. NP contributed to serial plating experimental work on Tet2-mutant progenitor cells. MW contributed to the bioinformatics analysis in AML database. SH analyzed the data. ATL directed all experimental activity and contributed to data interpretation, analysis, and writing of manuscript.

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Correspondence to A. Thomas Look.

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Jing, CB., Fu, C., Prutsch, N. et al. Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells (HSPCs) with TOP1-targeted drugs and PARP1 inhibitors. Leukemia 34, 2992–3006 (2020). https://doi.org/10.1038/s41375-020-0927-5

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