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Effect of pharmacologic inhibition of KPNB1 by Importazole on gene expression of NB-4 cells

ABSTRACT: Acute myeloid leukemia (AML) is the most common malignancy of the hematologic system with refractory relapse and limited treatments. Nucleocytoplasmic trafficking of biomolecules mediated by Karyopherin proteins plays vital roles in AML promotion and development, but the underlying mechanism is not clearly elucidated. KPNB1, a key member of Karyopherin beta subunits, is highly expressed in multiple cancers. Here, we found that elevated expression of KPNB1 correlates with unfavorable outcomes in patients with AML, and KPNB1 knockdown induces growth blocked and apoptosis in AML cells in vitro. In addition, pharmacologic inhibition of KPNB1 reduces tumor burden and extends survival in an MLL-AF9 leukemia model by KPNB1-specific inhibitor importazole (IPZ) in vivo. Moreover, KPNB1 inhibition by IPZ sensitizes AML cell lines and patients' cells to venetoclax. At the molecular level, KPNB1 directly binds to and mediates the nuclear import of HMGB2, a modulator of DNA repair. The inhibition of KPNB1 blocks the nuclear import of HMGB2 and consequently induces DNA damage in AML cells. Overall, our work elicits that inhibition of KPNB1-mediated HMGB2 nuclear translocation disrupts DNA damage repair and validates a potential target for treating AML therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277912 | GEO | 2025/01/08

REPOSITORIES: GEO

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