title: Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richmond
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: High
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Agnes
authors.initials: A
authors.lastname: Mendomo
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Alissa
authors.initials: A
authors.lastname: Robbins
authors.affiliation: Institute of Pharmaceutical Biology/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Venn
authors.affiliation: Institute of Pharmaceutical Biology/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Henderson
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, Australia.
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Kees
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia. rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D056750:Cyclin A1 / Q000096:biosynthesis; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D048288:Imidazolines / Q000627:therapeutic use*; D007223:Infant; D019169:Jurkat Cells; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C503747:Ccna1 protein, mouse; D056750:Cyclin A1; D018398:Homeodomain Proteins; D048288:Imidazolines; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C579783:RG7112; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; D011495:Histone-Lysine N-Methyltransferase; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2