Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia.
Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia.
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DOI：
10.1158/1078-0432.ccr-14-2300
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发表时间：
2015-03-15
期刊：
影响因子：
--
通讯作者：
Lock RB
中科院分区：
文献类型：
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作者：
Richmond J;Carol H;Evans K;High L;Mendomo A;Robbins A;Meyer C;Venn NC;Marschalek R;Henderson M;Sutton R;Kurmasheva RT;Kees UR;Houghton PJ;Smith MA;Lock RB
虽然儿科急性淋巴细胞白血病（ALL）的总体治愈率接近90%，但携带混合谱系白血病（MLL）癌基因易位的ALL婴儿（婴儿MLL-ALL）的缓解持续时间较短，生存率较低（0.50%）。p53肿瘤抑制基因突变在婴儿MLL-ALL中并不常见，从抑制机制中释放p53的药物可能是有益的。本研究的目的是评估口服nutlin（RG 7112）对患者源性MLL-ALL异种移植物的疗效。在免疫缺陷小鼠中建立了8个MLL-ALL患者来源的异种移植物，并将其分子特征与B系ALL和T-ALL异种移植物进行了比较。在体外和体内评估了MLL-ALL异种移植物对RG 7112的敏感性，并评价了RG 7112在体内诱导p53、细胞周期阻滞和细胞凋亡的能力。基因表达分析显示，MLL-ALL、B系ALL和T-ALL异种移植物根据亚型聚集。此外，先前报道在MLL-ALL中过表达的基因，包括MEIS 1、CCNA 1和HOXA家族成员，在MLL-ALL异种移植物中显著上调，证实了它们重现临床疾病的能力。MLL-ALL异种移植物在体内暴露于RG 7112引起p53上调、细胞周期停滞和细胞凋亡。RG 7112作为单药在婴儿MLL-ALL异种移植物中诱导显著消退。当使用诱导型方案（长春新碱/地塞米松/L-天冬酰胺酶）联合治疗评估RG 7112对MLL-ALL异种移植物的治疗增强时，观察到治疗增强。靶向p53-MDM 2轴与已确定的药物联合治疗婴儿MLL-ALL的效用值得进一步研究。
While the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell cycle arrest and apoptosis in vivo was evaluated. Gene expression analysis revealed that MLL-ALL, B-lineage ALL and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be over-expressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly up-regulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 up-regulation, cell cycle arrest and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation.