51. RUNX1 transactivates BCR‐ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia.
- Author
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Masuda, Tatsuya, Maeda, Shintaro, Shimada, Sae, Sakuramoto, Naoya, Morita, Ken, Koyama, Asami, Suzuki, Kensho, Mitsuda, Yoshihide, Matsuo, Hidemasa, Kubota, Hirohito, Kato, Itaru, Tanaka, Kuniaki, Takita, Junko, Hirata, Masahiro, Kataoka, Tatsuki R, Nakahata, Tatsutoshi, Adachi, Souichi, Hirai, Hideyo, Mizuta, Shuichi, and Naka, Kazuhito
- Abstract
The emergence of tyrosine kinase inhibitors as part of a front‐line treatment has greatly improved the clinical outcome of the patients with Ph+ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR‐ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)‐resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR‐ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb‐M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR‐ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR‐ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb‐M' consistently downregulated the expression of BCR‐ABL1 in these cells and this drug was highly effective even in an imatinib‐resistant Ph+ ALL cell line. In good agreement with these findings, forced expression of BCR‐ABL1 in these cells conferred relative resistance to Chb‐M'. In addition, in vivo experiments with the Ph+ ALL patient‐derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR‐ABL1. Chb‐M' could be a novel drug for patients with TKI‐resistant refractory Ph+ ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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