Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma
Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma
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DOI：
10.1182/blood-2016-09-741983
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发表时间：
2017-08-31
期刊：
影响因子：
20.3
通讯作者：
Iida, Shinsuke
中科院分区：
文献类型：
--
作者：
Narita, Tomoko;Ishida, Takashi;Iida, Shinsuke
细胞周期蛋白依赖性激酶9（CDK 9）是正转录延伸因子B（P-TEF B）复合物的一个亚基，通过磷酸化RNA聚合酶II（RNAP II）的C-末端结构域（CTD）来调节基因转录延伸。CDK 9/PTEFb的失调对许多癌症类型具有重要意义。BAY 1143572是一种新型高选择性CDK 9/P-TEFb抑制剂，目前正在I期研究中进行研究。我们评估了BAY 1143572在成人T细胞白血病/淋巴瘤（ATL）中的治疗潜力。由于CDK 9抑制和随后RNAPII CTD丝氨酸2磷酸化的抑制，BAY 1143572降低了ATL衍生的或人T细胞嗜淋巴细胞病毒1型（HTLV-1）转化的细胞系和原代ATL细胞中的c-Mycand Mcl-1水平，导致其生长抑制和凋亡。BAY 1143572在ATL衍生的或HTLV-1转化的细胞系（n = 8）、原代ATL细胞（n=11）和来自健康志愿者的CD 4 - 1细胞（n=5）中的中位抑制浓度分别为0.535、0.30和0.36 mM。接下来，NOG小鼠用作来自ATL患者的肿瘤细胞的受体。与未给药小鼠相比，BAY 1143572给药的ATL荷瘤小鼠（每日一次，12.5 mg/kg经口给药）显示肝脏和骨髓的ATL细胞浸润显著减少，血清中人可溶性白细胞介素-2受体水平降低（反映ATL肿瘤负荷）（两种均为n = 8）。BAY 1143572处理的ATL荷瘤小鼠的存活时间显著长于未处理的ATL荷瘤小鼠（两组均为n=7）。总的来说，本研究表明BAY 1143572作为ATL的一种新治疗方法显示出很强的潜力。
Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/PTEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. Weevaluated the therapeutic potential ofBAY1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY1143572 decreased c-Mycand Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n=11), and CD4 1 cells fromhealthy volunteers (n=5) were 0.535, 0.30, and 0.36 mM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearingmice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n=7 for both). Collectively, this study indicates thatBAY1143572showedstrongpotential as anovel treatmentof ATL.