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The prognostic significance of p16 INK4a /p14 ARF locus deletion and MDM‐2 protein expression in adult acute myelogenous leukemia
Author(s) -
Faderl Stefan,
Kantarjian Hagop M.,
Estey Elihu,
Manshouri Taghi,
Chan ChingYang,
Rahman Elsaied Abdel,
Kornblau Steven M.,
Cortes Jorge,
Thomas Deborah A.,
Pierce Sherry,
Keating Michael J.,
Estrov Zeev,
Albitar Maher
Publication year - 2000
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20001101)89:9<1976::aid-cncr14>3.0.co;2-n
Subject(s) - p14arf , myeloid leukemia , locus (genetics) , medicine , blot , cancer research , microbiology and biotechnology , leukemia , tumor suppressor gene , biology , gene , cancer , carcinogenesis , genetics
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. Cancer 2000;89:1976–82. © 2000 American Cancer Society.