Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import

Acute myeloid leukemia (AML) represents the most prevalent malignancy within the hematologic system, characterized by refractory relapses and a scarcity of effective treatment options. Karyopherin subunit beta-1 (KPNB1) is a member of karyopherin β family, mediating the nuclear import of its cargoes. In this study, we found that elevated expression levels of KPNB1 are associated with unfavorable outcomes in patients with AML. The knockdown of KPNB1 resulted in growth inhibition and apoptosis in AML cells. Additionally, pharmacological inhibition of KPNB1 using the specific inhibitor importazole (IPZ) significantly reduced tumor burden and prolonged survival in MLL-AF9-induced AML mice. Notably, the inhibition of KPNB1 by IPZ significantly enhanced the sensitivity of both AML cell lines and patient-derived cells to venetoclax in vitro and in xenograft mice models. At the molecular level, we identified an unrecognized cargo of KPNB1, high mobility group 2 (HMGB2), which plays a crucial role in DNA damage repair. Inhibition of KPNB1 resulted in impaired nuclear import of HMGB2, eventually leading to compromised DNA damage repair in AML cells. Overall, our findings elucidate the essential roles of KPNB1 in AML cells through the HMGB2-DNA damage repair axis and highlight a promising therapeutic target for AML intervention.