Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells
Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells
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DOI：
10.1182/blood-2008-06-164582
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发表时间：
2010-03-18
期刊：
影响因子：
20.3
通讯作者：
Holyoake, Tessa L.
中科院分区：
文献类型：
--
作者：
Heaney, Nicholas B.;Pellicano, Francesca;Holyoake, Tessa L.
酪氨酸激酶抑制剂（TKIs）有效治疗慢性髓性白血病（CML）；然而，仍存在2个关键问题- CML干细胞和祖细胞对tki不敏感以及tki耐药BCR-ABL突变的出现。BCR-ABL活性与蛋白酶体活性增加有关，蛋白酶体抑制剂（PIs）对CML细胞系具有细胞毒性。我们证明硼替佐米具有抗增殖作用，并在临床可达到的浓度下诱导慢性CD34(+) CML细胞凋亡。我们还发现硼替佐米靶向原始CML细胞，对CD34(+)38（-）、长期培养启动（LTC-IC）和非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）再填充细胞有影响。硼替佐米对CML细胞无选择性，可诱导正常CD34(+)38（-）细胞凋亡。当硼替佐米单独使用和与达沙替尼联合使用时，可以看到对CML细胞的影响。硼替佐米对表达BCR-ABL突变的细胞系（包括T315I）具有抑制蛋白酶体活性和诱导凋亡的作用，但对BCR-ABL没有抑制作用。通过靶向tki不敏感的干细胞和祖细胞以及tki耐药的BCR-ABL突变，我们相信硼替佐米为CML提供了一种潜在的治疗选择。由于已知的毒性，包括骨髓抑制，硼替佐米在CML中的最初临床应用可能是在耐药和晚期疾病中。(血。2010;115:2241 - 2250)
Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain-the insensitivity of CML stem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34(+) CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34(+)38(-), long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34(+)38(-) cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease. (Blood. 2010;115:2241-2250)