Madhumathi Jayaprakasam, Sridevi Surapally, Verma Rama Shanker
Bhupat & Jyoti Mehta School of Biosciences Building, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
Bhupat & Jyoti Mehta School of Biosciences Building, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
Stem Cell Res. 2017 Mar;19:65-75. doi: 10.1016/j.scr.2017.01.001. Epub 2017 Jan 4.
Chemotherapy resistant leukemic stem cells (LSCs) are being targeted as a modern therapeutic approach to prevent disease relapse. LSCs isolated from methotrexate resistant side population (SP) of leukemic cell lines HL60 and MOLT4 exhibited high levels of CD25 and TRAIL R2/DR5 which are potential targets. Recombinant immunotoxin conjugating IL2α with TRAIL peptide mimetic was constructed for DR5 receptor specific targeting of LSCs and were tested in total cell population and LSCs. IL2-TRAIL peptide induced apoptosis in drug resistant SP cells from cell lines and showed potent cytotoxicity in PBMCs derived from leukemic patients with an efficacy of 81.25% in AML and 100% in CML, ALL and CLL. IL2-TRAIL peptide showed cytotoxicity in relapsed patient samples and was more effective than TRAIL or IL2-TRAIL proteins. Additionally, DR5 specific IL2-TRAIL peptide was effective in targeting and killing LSCs purified from cell lines [IC50: 952nM in HL60, 714nM in MOLT4] and relapsed patient blood samples with higher efficacy (85%) than IL2-TRAIL protein (46%). Hence, CD25 and DR5 specific targeting by IL2-TRAIL peptide may be an effective strategy for targeting drug resistant leukemic cells and LSCs.
化疗耐药白血病干细胞（LSCs）正成为预防疾病复发的一种现代治疗靶点。从白血病细胞系HL60和MOLT4的甲氨蝶呤耐药侧群（SP）中分离出的LSCs表现出高水平的CD25和TRAIL R2/DR5，它们是潜在的靶点。构建了将IL2α与TRAIL肽模拟物偶联的重组免疫毒素，用于对LSCs进行DR5受体特异性靶向，并在全细胞群体和LSCs中进行了测试。IL2-TRAIL肽可诱导细胞系耐药SP细胞凋亡，并对白血病患者来源的外周血单个核细胞（PBMCs）显示出强大的细胞毒性，对急性髓系白血病（AML）的疗效为81.25%，对慢性髓系白血病（CML）、急性淋巴细胞白血病（ALL）和慢性淋巴细胞白血病（CLL）的疗效为100%。IL2-TRAIL肽在复发患者样本中显示出细胞毒性，且比TRAIL或IL2-TRAIL蛋白更有效。此外，DR5特异性IL2-TRAIL肽在靶向和杀死从细胞系中纯化的LSCs方面有效[HL60中的IC50：952nM，MOLT4中的IC50：714nM]，对复发患者血液样本的疗效（85%）高于IL2-TRAIL蛋白（46%）。因此，IL2-TRAIL肽对CD25和DR5的特异性靶向可能是靶向耐药白血病细胞和LSCs的有效策略。
