Protein expression of a triad of frequently methylated genes, p73, p57Kip2, and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status.
OBJECTIVE
To study the relationship between protein expression and DNA methylation of a triad of cell-cycle regulatory genes known to be frequently methylated in adult acute lymphocytic leukemia (ALL).


METHODS
Protein expression of p73, p15, and p57Kip2 was analyzed by immunohistochemistry using a tissue microarray (TMA) platform. The TMA was constructed using pretreatment bone marrow biopsy specimens from 64 adult patients with ALL. Protein expression was then correlated with DNA methylation and relevant clinical biologic characteristics.


RESULTS
p73 protein expression was observed in 19 (30%) patients, cytoplasmic p15 in 19 (31%), and p57 in 40 (70%). Three patients (5%) had expression of all three proteins, 16 (29%) of two proteins, 31 (55%) of one protein, and six (11%) of zero proteins. An inverse association was observed between p73 DNA methylation and protein expression (P = .003). This effect was not observed for either p15 or p57Kip2. Expression of any of the proteins studied was not associated with any distinct biologic characteristic. By multivariate analysis, expression of p57Kip2, cytoplasmic p15, or a combination of p57Kip2 with either p15 or p73 was associated with a better overall survival (P < .001, .04, and .03 respectively).


CONCLUSIONS
Expression of a triad of cell cycle regulatory proteins that includes p73, p15, and p57Kip2 has prognostic value in adult patients with ALL independently of the methylation status of each gene.
Bueso-Ramos
Carlos
C
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA.
Xu
Yunling
Y
McDonnell
Timothy J
TJ
Brisbay
Shawn
S
Pierce
Sherry
S
Kantarjian
Hagop
H
Rosner
Gary
G
Garcia-Manero
Guillermo
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; C493964:CDKN1C protein, human; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins