文章：

HSP90抑制剂NVP-BEP800影响SRC激酶的稳定性以及T细胞和B细胞急性淋巴细胞白血病的生长

HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias

原文发布日期：2021-03-18

DOI: 10.1038/s41408-021-00450-2

类型: Article

开放获取: 是

英文摘要：

T-cell and B-cell acute lymphoblastic leukemias (T-ALL, B-ALL) are aggressive hematological malignancies characterized by an accumulation of immature T- or B-cells. Although patient outcomes have improved, novel targeted therapies are needed to reduce the intensity of chemotherapy and improve the prognosis of high-risk patients. Using cell lines, primary cells and patient-derived xenograft (PDX) models, we demonstrate that ALL cells viability is sensitive to NVP-BEP800, an ATP-competitive inhibitor of Heat shock protein 90 (HSP90). Furthermore, we reveal that lymphocyte-specific SRC family kinases (SFK) are important clients of the HSP90 chaperone in ALL. When PDX mice are treated with NVP-BEP800, we found that there is a decrease in ALL progression. Together, these results demonstrate that the chaperoning of SFK by HSP90 is involved in the growth of ALL. These novel findings provide an alternative approach to target SRC kinases and could be used for the development of new treatment strategies for ALL.
 

摘要翻译： 

T细胞与B细胞急性淋巴细胞白血病（T-ALL、B-ALL）是侵袭性血液恶性肿瘤，其特征为未成熟T细胞或B细胞的异常积聚。尽管患者治疗效果已有所改善，仍需要新型靶向疗法以降低化疗强度并改善高风险患者的预后。通过细胞系、原代细胞及患者来源的异种移植模型研究，我们证实ALL细胞存活率对热休克蛋白90的ATP竞争性抑制剂NVP-BEP800具有敏感性。此外，我们发现淋巴细胞特异性SRC家族激酶是HSP90分子伴侣在ALL中的关键底物蛋白。使用NVP-BEP800处理PDX小鼠模型后，观察到ALL进展受到抑制。这些结果表明HSP90对SRC激酶的分子伴侣作用参与ALL的生长进程。该新发现为靶向SRC激酶提供了替代途径，可能推动ALL新治疗策略的开发。

原文链接：

HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias