title: p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells.
abstract: Philadelphia chromosome positive chronic myeloid leukemia has a progressive course starting in a benign phase and terminating in a blastic phase. In this study, we show that human homolog double minute 2 (HDM2) inhibition, with MI-219-a novel compound, and consequently p53 stabilization induce chronic myeloid leukemia (CML) blast crisis cells to undergo apoptosis regardless of the presence of the T315I mutation in the BCR-ABL kinase domain. The response to MI-219 is associated with the downregulation of c-Myc and the induction of p21(WAF1). The p53 target and pro-apoptotic proteins PUMA, Noxa and Bax are induced, whereas full length Bid protein decreases with increased activity of pro-apoptotic cleaved Bid, and decrease of Mcl-1 is observed by increased caspase activity. CD95/FAS (FAS antigen) receptor is also induced by MI-219, indicating that both intrinsic and extrinsic apoptotic responses are transcriptionally induced. In addition, p53 protein accumulates in the mitochondrial fraction of treated cells involved in transcription-independent induction of apoptosis. We conclude that HDM-2 inhibition with MI-219 effectively induces p53-dependent apoptosis in most blast crisis CML cells, with or without BCR-ABL mutation(s).
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Peterson
authors.forename: E
authors.initials: E
authors.lastname: Mitrikeska
authors.forename: D
authors.initials: D
authors.lastname: Giannola
authors.forename: Y
authors.initials: Y
authors.lastname: Lui
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: D
authors.initials: D
authors.lastname: Bixby
authors.forename: S N
authors.initials: SN
authors.lastname: Malek
authors.forename: N J
authors.initials: NJ
authors.lastname: Donato
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001752:Blast Crisis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D016313:Genes, abl; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D007211:Indoles; C551433:MI-291; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2