MDM2 SNP 309 Is Not Associated with Increased Expression Levels of MDM2 Nor Clinical Significance in Childhood Acute Lymphoblastic Leukemia

Previously, we reported that MDM2 overexpression by pediatric acute lymphoblastic leukemia (ALL) cells is linked to a poor response to chemotherapy and early relapse of disease. It was recently shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter, SNP309, was related to increased MDM2 expression and poor outcomes for various malignancies. The present retrospective study investigates the association of SNP 309 with MDM2 expression levels and clinical significance in pediatric ALL. Data obtained from 81 children with ALL showed a similar genotype distribution of SNP 309 as seen in other types of cancer and healthy populations: 37 T/T (46%), 37 T/G (46%) and 7 G/G (8%). However, this SNP did not seem to control MDM2 mRNA expression in ALL. We observed that 20 of the 81 ALL cases overexpressed MDM2 mRNA (> 10-fold higher than in normal bone marrow mononuclear cells), of which 8 were SNP 309 T/T, while 12 were T/G (10) or G/G (2) (p>0.5). Furthermore, we found that both MDM2 mRNA and protein were undetectable in 10 of 37 T/G and 3 of the 7 G/G cases. In addition, there were no associations found between SNP 309 and the in vitro response to doxorubicin, nor and early relapse in the 81 ALL patients. Upon review of 23 ALL cell lines, we found there was a relatively higher percentage of T/G (57%) than in fresh ALL samples (46%). However, the expression level of MDM2 was not related to SNP 309, but was rather closely associated with p53 status: All 11 ALL lines with wild-type p53 overexpressed MDM2 and all 12 ALL lines with mutant p53 or with a p53-null phenotype expressed no or low levels of MDM2, regardless of their SNP 309 status. These results suggest that in pediatric ALL, the SNP 309 status affects neither the expression of MDM2 nor the clinical prognosis.