Targeting HDAC8 sensitizes tyrosine kinase inhibitors in the elimination of B-cell acute lymphoblastic leukemia cells through degradation of HIF-1α

IF 13.4 1区 医学 Q1 HEMATOLOGY
Guilin Xu, Feng Wang, Ming Chen, Wenhui Gao, Ying Liu, Jiayan Zhu, Churan Wang, Huimin Jiang, Yunxuan Li, Peitao Zhang, Jian Yuan, Tingting Zhang, Chenxi Zhao, Lining Wang, Ling Wang, Jieling Jiang, Wenbin Cao, Zhuan Zhang, Haigen Fu, Ting Dong, Jiong Hu, Ke Li
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Abstract

Tyrosine kinase inhibitors (TKIs) only partially inhibit the growth of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) cells, and often lead to rapid relapse. Therefore, it is essential to elucidate the mechanisms of resistance and develop novel treatment strategies. Histone deacetylases (HDACs) are often dysregulated in hematological malignancies, and many HDAC inhibitors have shown potent antitumor activities. In this study, we found that HDAC8 was highly expressed in Ph+ B-ALL patient samples upon TKI treatment. HDAC8 inhibition significantly increased TKI-mediated elimination of leukemia cells and decreased their ability to initiate leukemia. Using two mouse models, we demonstrated that TKIs in combination with targeting HDAC8 effectively inhibited leukemia progression and reduced the frequencies of stem cells. Mechanistically, HDAC8 deacetylated hypoxia inducible factor-1α (HIF-1α) at lysine 19/21, leading to a reduction in PHD2-mediated hydroxylation and subsequent pVHL-mediated ubiquitination, which slowed the degradation of HIF-1α. HIF-1α inhibition induced apoptosis and decreased the initiating capacity of leukemia cells. Importantly, in a Ph+ B-ALL patient–derived xenograft model, targeting HDAC8 or HIF-1α in combination with TKIs significantly inhibited leukemia progression. In conclusion, our study revealed that targeting HDAC8/HIF-1α in combination with TKIs could be a promising strategy for treating Ph+ B-ALL.

Abstract Image

靶向HDAC8使酪氨酸激酶抑制剂增敏,通过降解HIF-1α消除b细胞急性淋巴细胞白血病细胞
酪氨酸激酶抑制剂(TKIs)仅部分抑制费城染色体阳性b细胞急性淋巴细胞白血病(Ph+ B-ALL)细胞的生长,并经常导致快速复发。因此,阐明耐药机制和开发新的治疗策略至关重要。组蛋白去乙酰化酶(HDAC)在血液系统恶性肿瘤中经常失调,许多HDAC抑制剂显示出有效的抗肿瘤活性。本研究发现,经TKI治疗后,HDAC8在Ph+ B-ALL患者样本中高表达。抑制HDAC8显著增加tki介导的白血病细胞消除,降低其引发白血病的能力。通过两种小鼠模型,我们证明了TKIs与靶向HDAC8的组合有效地抑制了白血病的进展并降低了干细胞的频率。机制上,HDAC8在赖氨酸19/21处脱乙酰化了缺氧诱导因子-1α (HIF-1α),导致phd2介导的羟基化和随后pvhl介导的泛素化减少,从而减缓了HIF-1α的降解。抑制HIF-1α可诱导白血病细胞凋亡,降低白血病细胞的启动能力。重要的是,在Ph+ B-ALL患者来源的异种移植模型中,靶向HDAC8或HIF-1α联合TKIs可显著抑制白血病进展。总之,我们的研究表明靶向HDAC8/HIF-1α联合TKIs可能是治疗Ph+ B-ALL的一种有希望的策略。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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