Hematology (Amsterdam, Netherlands) · 2026
XPO1 inhibitor selinexor suppresses homologous recombination by inhibiting E2F7 nuclear export in acute myeloid leukemia.
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Xu Chunli, Wang Dandan, Chen Ruiqi, Feng Xu, Cheng Feng, Chen Yu
Аннотация
OBJECTIVES: Aberrant nucleocytoplasmic transport mediated by Exportin 1 (XPO1) contributes to leukemogenesis, yet the molecular basis underlying the limited efficacy of the XPO1 inhibitor Selinexor in acute myeloid leukemia (AML) remains unclear. This study aimed to define the role of XPO1 in AML and elucidate the mechanism by which Selinexor regulates homologous recombination (HR).
METHODS: Public AML datasets and patient samples were analyzed to assess XPO1 expression and clinical relevance. Functional assays evaluated the effects of XPO1 knockdown on AML cell proliferation, apoptosis, and cell cycle progression. Transcriptomic analysis, immunoprecipitation, subcellular fractionation, DNA damage assays, and direct HR functional assays were used to investigate Selinexor-mediated mechanisms. Drug interaction analyses assessed the combined effect of Selinexor and Mitoxantrone.
RESULTS: XPO1 was significantly overexpressed in AML, particularly in relapsed cases, and high expression was associated with poor prognosis. XPO1 knockdown suppressed proliferation, induced apoptosis, and caused cell cycle arrest. High XPO1 expression correlated with activation of the HR pathway. Mechanistically, Selinexor disrupted the interaction between XPO1 and the transcriptional repressor E2F7, resulting in nuclear retention of E2F7 and downregulation of BRCA1 and RAD51. E2F7 silencing reversed Selinexor-induced HR suppression and DNA damage. In addition, Selinexor synergized with Mitoxantrone to enhance DNA damage and apoptosis in AML cells.
DISCUSSION: E2F7-mediated HR inhibition is a key mechanism underlying Selinexor activity in AML.
CONCLUSION: The XPO1-E2F7-HR axis represents a potential therapeutic vulnerability, supporting the rational combination of Selinexor with DNA-damaging agents to improve AML treatment outcomes.
METHODS: Public AML datasets and patient samples were analyzed to assess XPO1 expression and clinical relevance. Functional assays evaluated the effects of XPO1 knockdown on AML cell proliferation, apoptosis, and cell cycle progression. Transcriptomic analysis, immunoprecipitation, subcellular fractionation, DNA damage assays, and direct HR functional assays were used to investigate Selinexor-mediated mechanisms. Drug interaction analyses assessed the combined effect of Selinexor and Mitoxantrone.
RESULTS: XPO1 was significantly overexpressed in AML, particularly in relapsed cases, and high expression was associated with poor prognosis. XPO1 knockdown suppressed proliferation, induced apoptosis, and caused cell cycle arrest. High XPO1 expression correlated with activation of the HR pathway. Mechanistically, Selinexor disrupted the interaction between XPO1 and the transcriptional repressor E2F7, resulting in nuclear retention of E2F7 and downregulation of BRCA1 and RAD51. E2F7 silencing reversed Selinexor-induced HR suppression and DNA damage. In addition, Selinexor synergized with Mitoxantrone to enhance DNA damage and apoptosis in AML cells.
DISCUSSION: E2F7-mediated HR inhibition is a key mechanism underlying Selinexor activity in AML.
CONCLUSION: The XPO1-E2F7-HR axis represents a potential therapeutic vulnerability, supporting the rational combination of Selinexor with DNA-damaging agents to improve AML treatment outcomes.