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

Area of Science:

• Hematology
• Cancer Biology
• Pharmacology

Background:

• TET2 inactivating mutations initiate hematopoietic stem and progenitor cell (HSPC) transformation.
• Targeting these mutant cells is crucial for treating TET2-mutant hematologic malignancies.

Purpose of the Study:

• To identify drugs that selectively kill TET2-mutant HSPCs in vivo.
• To evaluate the therapeutic potential of exportin 1 (XPO1) inhibitors for TET2-mutant cancers.

Main Methods:

• Drug screening in zebrafish embryos to identify compounds targeting tet2-mutant HSPCs.
• In vitro colony assays using murine Tet2-deficient LSK cells and human TET2-inactivated AML cells.
• Assessment of apoptosis and DNA damage (γH2AX expression) following drug treatment.

Main Results:

• Exportin 1 (XPO1) inhibitors, selinexor and eltanexor, demonstrated selective killing of TET2-mutant HSPCs and AML cells.
• The mechanism involves increased apoptosis without significant DNA damage.
• These findings were consistent across zebrafish, murine, and human cell models.

Conclusions:

• TET2 loss sensitizes HSPCs and AML cells to XPO1 inhibitors, indicating a novel therapeutic vulnerability.
• XPO1 inhibitors show preclinical promise for treating TET2-mutant hematologic malignancies and clonal hematopoiesis.
• Further clinical studies are warranted to explore selinexor and eltanexor for these conditions.