Barwe Sonali P, Huang Fei, Kolb Edward Anders, Gopalakrishnapillai Anilkumar
Nemours Centers for Childhood Cancer Research and Cancer & Blood Disorders, Nemours Children's Health, Wilmington, DE 19803, USA.
Geron Corporation, Parsippany, NJ 07054, USA.
J Clin Med. 2022 Mar 30;11(7):1923. doi: 10.3390/jcm11071923.
Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.
尽管采用了最大强度的治疗方法，儿童急性髓系白血病（AML）仍然是致命的。由于白血病干细胞（LSC）对化疗耐药性和复发有显著影响，专门针对LSC的治疗方法可能对改善预后更有益。已知LSC具有高端粒酶活性，并且端粒酶活性与儿童AML的生存率呈负相关。我们评估了端粒酶活性寡核苷酸抑制剂艾美拉唑在儿童AML患者来源异种移植（PDX）模型中的临床前疗效。在六个儿童AML PDX模型中，艾美拉唑治疗在体外以剂量依赖性方式显著增加了LSC群体的凋亡/死亡，而对正常骨髓标本中的干细胞群体活性有限。这些结果在两个不同的PDX模型中得到了体内验证，其中艾美拉唑作为单一药物或与化疗联合使用可大大降低LSC百分比并延长中位生存期。艾美拉唑与DNA低甲基化剂阿扎胞苷联合使用也有助于延长生存期。二次移植实验表明，接受艾美拉唑治疗细胞的小鼠移植延迟且生存期延长，证实了LSC群体减少。因此，我们的数据表明艾美拉唑是儿童AML的一种有效治疗策略。
