The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia

BACKGROUND. The p16(INK4a) locus encodes two distinct proteins, p16(INK4a) and p14(ARF). Although p16(INK4a) and p15(INK4b) involved in the phosphoryl ation 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. West ern blotting was used to determine Rb protein phosphorylation in patients w ith 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 o f 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 dura tion (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) we re significantly shorter in patients with deletions of p16(INK4a)/p14(ARF) andlor p15(INK4b). Thirty-seven (47%] of 79 patients studied for MDM-2 show ed increased MDM-2 expression These patients had a significantly shorter EF S 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 diffe rent (50 vs. 84 weeks; P = 0.136). CONCLUSIONS. The authors concluded that 1) deletions of p16(INK4a)/p14(ARF) andlor p15(INK4b) occur with low incidence in patients with AML; 2) patien ts with deletions of p16(INK4a)/p14(ARF) andlor p15(INK4b) have a significa ntly shorter CR duration, EFS rate, and overall survival rate than do patie nts 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 overexpre ssion may pray a role in the biology of the disease. (C) 2000 American Canc er Society.