Overcoming Tyrosine Kinase Inhibitor Resistance in Transformed Cell Harboring SEPT9-ABL1 Chimeric Fusion Protein

Hidetsugu Kawai, Hiromichi Matsushita, Rikio Suzuki, Yuka Kitamura, Yoshiaki Ogawa, Hiroshi Kawada, Kiyoshi Ando

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Hematological malignancies harboring various ABL1 fusions are expected to be sensitive to tyrosine kinase inhibitors (TKIs), similar to those with BCR-ABL1. However, SEPT9-ABL1 exhibits TKI resistance both in vitro and in vivo. SEPT9-ABL1 has the same ABL1 region as seen in BCR-ABL1 but no point mutation in its kinase domain, which is one of the main mechanisms underlying TKI resistance in the leukemic cells harboring BCR-ABL1. The purpose of this study was to reveal the mechanism underlying TKI resistance induced by SEPT9-ABL1. We focused on the TP53 status because TKI-induced apoptosis in BCR-ABL1–positive cells is achieved through TP53. Mouse TP53 homologue TRP53 was downregulated and less phosphorylated in the cells expressing SEPT9-ABL1 than in those with BCR-ABL1, resulting in the prevention of apoptosis induced by TKIs. The CRM1 inhibitor KPT-330 accumulated nuclear TRP53 and NFKB1A (also known as IκBα), which is thought to capture TRP53 in the cytoplasm, and induced apoptosis in the hematopoietic cells expressing SEPT9-ABL1. In addition, the combination treatment of KPT-330 and imatinib, which induced the marked nuclear accumulation of PP2A and SET, reactivated PP2A through its dephosphorylation and inhibited SET expression, resulting in the effective induction of the apoptosis in the cells expressing SEPT9-ABL1. The combination treatment with KPT-330 and imatinib successfully reduced the subcutaneous masses expressing SEPT9-ABL1 and extended the survival of the mice intraperitoneally transplanted with SEPT9-ABL1–expressing cells. These results show that therapy with CRM1 inhibitors may be effective for overcoming TKI resistance induced by SEPT9-ABL1.

Original languageEnglish
Pages (from-to)788-801
Number of pages14
JournalNeoplasia (United States)
Issue number8
Publication statusPublished - 2019 Aug
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research


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