Cruickshank M N, Ford J, Cheung L C, Heng J, Singh S, Wells J, Failes T W, Arndt G M, Smithers N, Prinjha R K, Anderson D, Carter K W, Gout A M, Lassmann T, O'Reilly J, Cole C H, Kotecha R S, Kees U R
Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
Leukemia. 2017 Jan;31(1):40-50. doi: 10.1038/leu.2016.165. Epub 2016 Jun 13.
To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage-response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL.
为了改善混合谱系白血病（MLL）重排的婴儿急性淋巴细胞白血病（iALL）的不良预后，我们从原发性患者样本中建立了一组细胞系，并研究了它们对当代及美国食品药品监督管理局批准的新型化疗药物的细胞毒性反应。为了表征细胞系中原发性疾病的特征，我们使用RNA测序和细胞遗传学比较了分子特征。高通量筛选揭示了目前使用药物的疗效各异，但确定了三种新型药物类别具有一致的疗效：蛋白酶体抑制剂、组蛋白去乙酰化酶抑制剂和细胞周期蛋白依赖性激酶抑制剂。将iALL细胞系与匹配的原发性标本进行比较，药物靶点的基因表达具有高度可重复性。包括罗米地辛（ROM）在内的组蛋白去乙酰化酶抑制剂在体外增强了iALL治疗关键成分阿糖胞苷（ARAC）的活性，并且将ROM和ARAC联合给药于异种移植小鼠可进一步减轻白血病负担。分子研究表明，ROM降低了参与ARAC失活的胞苷脱氨酶的表达，并增强了对ARAC的DNA损伤反应。总之，我们提供了一个有价值的药物发现资源，包括首次对体外转录组可重复性进行系统分析，并确定ROM是治疗MLL重排iALL的一种有前景的疗法。
