Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia
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Published on: October 17, 2025
Jennifer Richmond1, Hernan Carol1, Kathryn Evans1
1Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
Insights
RG7112, a p53-MDM2 axis inhibitor, showed efficacy in preclinical models of infant mixed-lineage leukemia (MLL)-ALL. Combination therapy with RG7112 enhanced treatment effects, suggesting its potential in managing infant MLL-ALL.
Area of Science:
- Pediatric Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Infant acute lymphoblastic leukemia (ALL) with mixed-lineage leukemia (MLL) oncogene translocations has poor outcomes despite high overall pediatric ALL cure rates.
- Mutations in the p53 tumor-suppressor gene are rare in infant MLL-ALL, suggesting alternative therapeutic strategies targeting p53 regulation may be beneficial.
Purpose of the Study:
- To evaluate the efficacy of RG7112, an oral nutlin inhibitor of the p53-MDM2 interaction, against patient-derived MLL-ALL xenografts.
- To assess the potential of RG7112 in combination with standard chemotherapy for infant MLL-ALL.
Main Methods:
- Established eight MLL-ALL patient-derived xenografts in immune-deficient mice.
- Assessed RG7112 sensitivity in vitro and in vivo, evaluating p53 induction, cell-cycle arrest, and apoptosis.
- Compared molecular features of MLL-ALL xenografts with B-lineage and T-ALL xenografts.
Main Results:
- Gene-expression analysis confirmed MLL-ALL xenografts recapitulated key molecular features of the clinical disease.
- In vivo RG7112 treatment induced p53 upregulation, cell-cycle arrest, and apoptosis in MLL-ALL xenografts.
- RG7112 monotherapy led to significant xenograft regressions, and combination therapy with standard induction agents showed enhanced therapeutic effects.
Conclusions:
- Targeting the p53-MDM2 axis with RG7112 demonstrates preclinical efficacy in infant MLL-ALL models.
- Combination therapy of RG7112 with established drugs warrants further investigation for improved infant MLL-ALL management.
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.
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