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小分子 E26 转化特异性抑制剂 TK216 可减弱小儿白血病的致癌特性。

The Small-Molecule E26-Transformation-Specific Inhibitor TK216 Attenuates the Oncogenic Properties of Pediatric Leukemia.

机构信息

Department of Oncology, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, AB T2N 4N1, Canada.

出版信息

Genes (Basel). 2023 Oct 8;14(10):1916. doi: 10.3390/genes14101916.

DOI:10.3390/genes14101916
PMID:37895265
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10606408/
Abstract

The E26-transformation-specific (ETS) transcription factors regulate multiple aspects of the normal hematopoietic system. There is an increasing body of evidence suggesting aberrant ETS activity and its contribution to leukemia initiation and progression. In this study, we evaluated the small-molecule ETS inhibitor TK216 and demonstrated its anti-tumor activity in pediatric leukemia. We found TK216 induced growth inhibition, cell cycle arrest and apoptosis and inhibited the migratory capability of leukemic cells, without significantly inhibiting the cell viability of normal blood mononuclear cells. Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells. Importantly, we found purine-rich box1 (PU.1) to be a potential target of TK216 in myeloid and B-lymphoid leukemic cells. In addition, TK216 sharply decreased Mcl-1 protein levels in a dose-dependent manner. Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia.

摘要

E26 转化特异性（ETS）转录因子调节正常造血系统的多个方面。越来越多的证据表明，异常的 ETS 活性及其对白血病起始和进展的贡献。在这项研究中，我们评估了小分子 ETS 抑制剂 TK216，并证明了其在儿科白血病中的抗肿瘤活性。我们发现 TK216 诱导了生长抑制、细胞周期停滞和细胞凋亡，并抑制了白血病细胞的迁移能力，而对正常血单核细胞的细胞活力没有显著抑制。用 5-氮杂胞苷对白血病细胞进行预处理增强了 TK216 对儿科白血病细胞的细胞毒性作用。重要的是，我们发现富含嘌呤的框 1（PU.1）是 TK216 在髓系和 B 淋巴细胞白血病细胞中的潜在靶标。此外，TK216 以剂量依赖性方式显著降低 Mcl-1 蛋白水平。与此一致，TK216 还增强了 Venetoclax 耐药细胞中 Bcl-2 抑制的细胞毒性作用。在骨髓衍生的条件培养基存在下，白血病细胞获得的持续生存益处也被发现可被 TK216 调节。总之，我们的数据表明，TK216 可能是治疗急性髓系和 B 淋巴细胞白血病的一种有前途的靶向治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/67dba133daa0/genes-14-01916-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/67dba133daa0/genes-14-01916-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/5cab976da311/genes-14-01916-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/f5275d7a1148/genes-14-01916-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/a4b7449a33f8/genes-14-01916-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/6ef4f86a21ce/genes-14-01916-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d29/10606408/589e9ed03d88/genes-14-01916-g006.jpg
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本文引用的文献

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