Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia

Akira Honda, Junji Koya, Akihide Yoshimi, Masashi Miyauchi, Kazuki Taoka, Keisuke Kataoka, Shunya Arai, Mineo Kurokawa

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Primary refractory acute myeloid leukemia (AML) is unresponsive to conventional chemotherapy and has a poor prognosis. Despite the recent identification of novel driver mutations and advances in the understanding of the molecular pathogenesis, little is known about the relationship between genetic abnormalities and chemoresistance in AML. In this study, we subjected 39 samples from patients with primary refractory AML to whole-exome and targeted sequencing analyses to identify somatic mutations contributing to chemoresistance in AML. First, we identified 49 genes that might contribute to chemotherapy resistance through the whole-exome sequencing of samples from 6 patients with primary refractory AML. We then identified a significantly higher frequency of mutations in the gene encoding BCL-6 co-repressor (BCOR) in patients with primary refractory AML through the targeted sequencing of all coding sequence of 49 genes. Notably, the presence of BCOR mutations appeared to have a negative impact on prognosis in our cohort and previous larger studies. Subsequently, to investigate the biological effect of BCOR mutations on sensitivity to anticancer drugs, we established BCOR knockout human leukemic cell lines using the CRISPR/Cas9 system. Here, BCOR knockout cell lines exhibited statistically significant reductions in sensitivity to anticancer drugs, compared with the wild-type controls both in vitro and in vivo in xenograft mouse models. In conclusion, loss-of-function BCOR mutations appear to contribute to chemotherapy resistance and may be a promising therapeutic target in primary refractory AML.

本文言語English
ページ(範囲)42-48.e11
ジャーナルExperimental Hematology
101-102
DOI
出版ステータスPublished - 2021 9月
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 血液学
  • 遺伝学
  • 細胞生物学
  • 癌研究

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