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Masanobu Tsubaki,Tomoya Takeda,Takuya Matsuda,Akihiro Kimura,Remi Tanaka,Sakiko Nagayoshi,Tadafumi Hoshida,Kazufumi Tanabe,Shozo Nishida 생화학분자생물학회 2023 BMB Reports Vol.56 No.2
Chronic myeloid leukemia (CML) has a markedly improvedprognosis with the use of breakpoint cluster region-abelson 1(BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However,approximately 40% of patients are resistant or intolerantto BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is ahypoxia response factor that has been reported to be highlyexpressed in CML patients, making it a therapeutic target forBCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors inducecell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death inBCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrationswhile the cell sensitivity was not affected with imatinibor dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition,echinomycin and PX-478 inhibited the c-Jun N-terminalkinase (JNK), Akt, and extracellular-regulated protein kinase 1/2(ERK1/2) activation via suppression of BCR-ABL1 and Met expressionin BCR-ABL1 sensitive and resistant CML cells. Moreover,treatment with HIF-1α siRNA induced cell death by inhibitingBCR-ABL1 and Met expression and activation of JNK,Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CMLcells. These results indicated that HIF-1α regulates BCR-ABL andMet expression and is involved in cell survival in CML cells,suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitorsare potential candidates for CML treatment.