The prognostic significance of p16INK4a/p14ARF locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia

BACKGROUND The p16INK4a locus encodes two distinct proteins, p16INK4a and p14ARF. Although p16INK4a and p15INK4b are involved in the phosphorylation of the retinoblastoma (Rb) protein, p14ARF interacts with the MDM-2 oncoprotein antagonizing its function as a suppressor of p53. The role of deletions of p16INK4a/p14ARF and p15INK4b and expressions of MDM-2 in myeloid leukemias and its influence on prognosis remain unclear. METHODS The authors analyzed deletions of p16INK4/p14ARF and p15INK4b 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 p16INK4/p14ARF and p15INK4b. 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 p16INK4a/p14ARF and/or p15INK4b 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 p16INK4a/p14ARF and/or p15INK4b. 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 p16INK4a/p14ARF and/or p15INK4b occur with low incidence in patients with AML; 2) patients with deletions of p16INK4a/p14ARF and/or p15INK4b 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 p14ARF 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.