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) 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.
Faderl
S
S
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Kantarjian
H M
HM
Estey
E
E
Manshouri
T
T
Chan
C Y
CY
Rahman Elsaied
A
A
Kornblau
S M
SM
Cortes
J
J
Thomas
D A
DA
Pierce
S
S
Keating
M J
MJ
Estrov
Z
Z
Albitar
M
M
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
D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2