The role of survivin in drug resistant pediatric acute lymphoblastic leukemia

Unrestricted Despite the recent advances in chemotherapy for acute lymphoblastic leukemia (ALL), drug resistance resulting in relapse and long-term side effects of current treatments warrant new treatment modalities. Survivin/BIRC5, an inhibitor of apoptosis (IAP) protein, is critical for the survival and proliferation of cancerous cells and has become the target of an increasing number of preclinical novel therapies against primarily solid tumors. Survivin is expressed in AML and ALL cells and has been implicated in leukemia relapse. We test the hypothesis that survivin is critical to the pathway of self-renewal and maintenance of drug resistant ALL cells. To address this hypothesis, we have developed a murine xenograft model of patient-derived ALL cells, which are referred to here as primary ALL cells, allowing us to assess novel therapies targeting survivin using non-invasive monitoring of leukemogenesis by bioluminescent imaging. Our data suggest that overexpression of survivin increases self-renewal and drug-resistance of patient-derived ALL cells in vitro and accelerates leukemogenesis in vivo. In addition, in vitro inhibition of survivin using shRNA strongly synergizes with conventional chemotherapy in patient-derived ALL cells and decreases self-renewal. In vivo inhibition of survivin prolongs survival of mice engrafted with drug resistant leukemia. Taken together, we show that survivin is a key component in drug-resistance and stem cell self-renewal of drug resistant ALL cells.

【无限制（Unrestricted）】尽管急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）的化疗近年来已取得进展，但当前治疗所引发的耐药性会导致疾病复发，且伴随长期副作用，因此亟需开发全新的治疗策略。生存素/Survivin/BIRC5作为凋亡抑制蛋白（inhibitor of apoptosis, IAP）家族成员，对癌细胞的存活与增殖至关重要，现已成为越来越多针对实体瘤的临床前新型疗法的热门靶点。生存素在急性髓系白血病（acute myeloid leukemia, AML）与ALL细胞中均有表达，且与白血病复发密切相关。本研究验证如下假说：生存素是耐药性ALL细胞自我更新与维持通路的关键调控因子。为验证该假说，我们构建了患者来源的ALL细胞（本文中称为原代ALL细胞）的小鼠异种移植模型，可通过生物发光成像无创监测白血病发生过程，以此评估针对生存素的新型治疗手段。本研究数据显示，生存素过表达可在体外增强患者来源ALL细胞的自我更新能力与耐药性，并在体内加速白血病发生进程。此外，在体外利用短发夹RNA（short hairpin RNA, shRNA）抑制生存素，可与常规化疗在患者来源ALL细胞中产生显著协同效应，并降低细胞自我更新能力。体内抑制生存素可延长移植耐药性白血病小鼠的存活时间。综上，本研究证实生存素是耐药性ALL细胞耐药性与干细胞自我更新过程的关键组成部分。