Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia

J. Richmond, H. Carol, K.E. Evans, L.M. High, A. Mendomo, A. Robbins, C. Meyer, N.C. Venn, R. Marschalek, M.J. Henderson, R. Sutton, R.T. Kurmasheva, Ursula Kees, P.J. Houghton, M.A. Smith, R.B. Lock

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Abstract

©2015 AACR. Purpose: Although 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. Experimental Design: 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. Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, 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. Conclusions: The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation.
Original languageEnglish
Pages (from-to)1395-1405
JournalClinical Cancer Research
Volume21
Issue number6
Early online date8 Jan 2015
DOIs
Publication statusPublished - 15 Mar 2015

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    Richmond, J., Carol, H., Evans, K. E., High, L. M., Mendomo, A., Robbins, A., Meyer, C., Venn, N. C., Marschalek, R., Henderson, M. J., Sutton, R., Kurmasheva, R. T., Kees, U., Houghton, P. J., Smith, M. A., & Lock, R. B. (2015). Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia. Clinical Cancer Research, 21(6), 1395-1405. https://doi.org/10.1158/1078-0432.CCR-14-2300