Münch Claudia, Dragoi Diana, Frey Anna-Verena, Thurig Katja, Lübbert Michael, Wäsch Ralph, Bogatyreva Lioudmila, Hauschke Dieter, Lassmann Silke, Werner Martin, May Annette M
Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany.
Department of Hematology and Oncology, University Medical Center, Hugstetter Str. 55, 79106 Freiburg, Germany.
Leuk Res. 2015 Apr;39(4):462-70. doi: 10.1016/j.leukres.2015.01.007. Epub 2015 Jan 28.
Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.
Polo样激酶1（PLK1）是细胞周期的重要调节因子，在各种实体瘤和血液系统恶性肿瘤中均有过表达。靶向PLK1的小分子抑制剂，如BI2536或BI6727（沃拉替尼），是治疗此类恶性肿瘤的一种有前景的治疗方法。在此，我们展示了在接受BI2536治疗后的AML患者骨髓活检中，AML原始细胞体内特异性定位的PLK1缺失，同时伴有有丝分裂停滞并转变为凋亡。我们在AML细胞系HL-60的活细胞成像实验中验证了这些结果，并证明非肿瘤性、永生化淋巴母细胞样细胞对PLK1抑制也敏感。结果表明，正常粒细胞前体的PLK1表达水平与白血病原始细胞相似。这些结果与PLK1抑制的不良反应一致，并强调了PLK1抑制剂在AML治疗中的巨大潜力。
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