title: Induction of p53 suppresses chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML.
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Luke F
authors.initials: LF
authors.lastname: Peterson
authors.affiliation: c College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Miao-Chia
authors.initials: MC
authors.lastname: Lo
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Giannola
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Emilija
authors.initials: E
authors.lastname: Mitrikeska
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.affiliation: d DNA Sequencing and Microarray Core , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Johnson
authors.affiliation: e Department of Pharmacology and Medicinal Chemistry , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mercer
authors.affiliation: a Comprehensive Cancer Center , University of Michigan , Ann Arbor , MI , USA.|b Department of Internal Medicine, Division of Hematology and Oncology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C574930:MI-219; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53
keywords: MI-219; chronic myeloid leukemia; p53