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 p16INK4a /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 ϭ 0.187), CR duration (10 vs. 46 weeks; P Ͻ 0.001), event free survival rate (EFS; 6 vs. 85 weeks; P Ͻ 0.004) and overall survival rate (11 vs. 86 weeks; P ϭ 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 ϭ 0.023) and a trend for shorter CR duration (24 vs. 53 weeks; P ϭ 0.07). Overall survival rate was not significantly different (50 vs. 84 weeks; P ϭ 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.

Prognostic significance of CDKN2A/B deletions in acute lymphoblastic leukaemia: a meta-analysis

“…CDKN2A/B are frequently deleted in both adult and childhood ALL. Although numerous studies have been conducted thus far evaluating the prognostic significance of CDKN2A/B deletions in ALL patients, the correlation is still under debate [12][13][14][15][16][17][18]. Thus, it is valuable to perform a meta-analysis to comprehensively assess the association between CDKN2A/B deletions and clinical outcome in ALL patients.…”

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

“…In de novo acute myeloid leukemia (AML), TP53 mutations are rare, occurring in less than 10% of patients (14)(15)(16)(17)(18). Although in some specific subsets of AML TP53 mutations are more frequent [for example, in up to 80% in patients with complex cytogenetics (19)], p53 inactivation more often results from the overexpression of its endogenous inhibitors MDMX or MDM2, which frequently occurs in p53 wild-type (WT) AML (20)(21)(22)(23)(24)(25)(26). It was recently reported that MDMX protein and mRNA are overexpressed in up to 92% of AML cases (27).…”

TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…However, while these mutations are rare in MDS/AML with a normal karyotype (1%), they are seen in 40–50% of secondary and therapy-related cases [ 20 , 25 , 26 , 27 ], and in 80% of complex monosomal karyotypes (CK) that include 17p and/or 5q deletion [ 28 , 29 ]. Other inactivating mechanisms of wild-type p53 function include overexpression of MDM2 and MDM4, negative regulators of p53, in 20–30% and 40–50% of AML cases, respectively [ 30 , 31 , 32 , 33 , 34 ]. Unfortunately, treatment with Mdm2 inhibitors has not so far demonstrated a substantial effect in these cases [ 35 ].…”