title: The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia.
abstract: BACKGROUND
  The p16(INK4a) locus encodes two distinct proteins, p16(INK4a) and p14(ARF). Although p16(INK4a) and p15(INK4b) are involved in the phosphorylation of the retinoblastoma (Rb) protein, p14(ARF) interacts with the MDM-2 oncoprotein antagonizing its function as a suppressor of p53. The role of deletions of p16(INK4a)/p14(ARF) and p15(INK4b) and expressions of MDM-2 in myeloid leukemias and its influence on prognosis remain unclear.
  
  
  METHODS
  The authors analyzed deletions of p16(INK4)/p14(ARF) and p15(INK4b) in 74 adults with acute myeloid leukemia (AML) by Southern blotting. Western blotting was used to determine Rb protein phosphorylation in patients with deletions of p16(INK4)/p14(ARF) and p15(INK4b). Then, they analyzed the levels of MDM-2 protein expression and correlated it with prognosis in an expanded population of 79 adults with AML by immunoblot analysis and solid-phase radioimmunoassay.
  
  
  RESULTS
  Deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occurred in 4 of 74 patients (5%) (hemizygous in 3, homozygous in 1 patient). Although the complete remission (CR) rate was similar (79% vs. 50%; P = 0.187), CR duration (10 vs. 46 weeks; P < 0.001), event free survival rate (EFS; 6 vs. 85 weeks; P < 0.004) and overall survival rate (11 vs. 86 weeks; P = 0.001) were significantly shorter in patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b). Thirty-seven (47%) of 79 patients studied for MDM-2 showed increased MDM-2 expression. These patients had a significantly shorter EFS rate (50 vs. 64 weeks; P = 0.023) and a trend for shorter CR duration (24 vs. 53 weeks; P = 0.07). Overall survival rate was not significantly different (50 vs. 84 weeks; P = 0.136).
  
  
  CONCLUSIONS
  The authors concluded that 1) deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occur with low incidence in patients with AML; 2) patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) have a significantly shorter CR duration, EFS rate, and overall survival rate than do patients without deletions; (3) overexpression of MDM-2 is common in AML and is associated with shorter CR duration and EFS rate. Mechanisms other than p14(ARF) deletion are responsible for MDM-2 overexpression, and this overexpression may play a role in the biology of the disease.
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: S
authors.initials: S
authors.lastname: Faderl
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: E
authors.initials: E
authors.lastname: Estey
authors.forename: T
authors.initials: T
authors.lastname: Manshouri
authors.forename: C Y
authors.initials: CY
authors.lastname: Chan
authors.forename: A
authors.initials: A
authors.lastname: Rahman Elsaied
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: D A
authors.initials: DA
authors.lastname: Thomas
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
authors.forename: M
authors.initials: M
authors.lastname: Albitar
mesh_terms: D000328:Adult; D015139:Blotting, Southern; D003582:Cytogenetics; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D019942:Genes, p16; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D009687:Nuclear Proteins; D011379:Prognosis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011863:Radioimmunoassay; D015996:Survival Rate; D025803:Tumor Suppressor Protein p14ARF
chemical_list: D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2