title: p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status.
abstract: TP53 mutations are associated with the lowest survival rates in acute myeloid leukemia (AML). In addition to mutations, loss of p53 function can arise via aberrant expression of proteins that regulate p53 stability and function. We examined a large AML cohort using proteomics, mutational profiling and network analyses, and showed that (1) p53 stabilization is universal in mutant TP53 samples, it is frequent in samples with wild-type TP53, and in both cases portends an equally dismal prognosis; (2) the p53 negative regulator Mdm2 is frequently overexpressed in samples retaining wild-type TP53 alleles, coupled with absence of p21 expression and dismal prognosis similar to that of cases with p53 stabilization; (3) AML samples display unique patterns of p53 pathway protein expression, which segregate prognostic groups with distinct cure rates; (4) such patterns of protein activation unveil potential AML vulnerabilities that can be therapeutically exploited.
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quintás-Cardama
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Qutub
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Post
authors.affiliation: Life Technologies Corporation, Carlsbad, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Coombes
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D040081:Protein Array Analysis; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2