Methylation of the multi tumor suppressor gene-2 (MTS2, CDKN1, p15INK4B) in childhood acute lymphoblastic leukemia.
The multi tumor suppressor genes MTS1 (CDKN2 p16INK4A) and MTS2 (CDKN1, p15INK4B) located at 9p21-22 are inactivated in some human cancers via several mechanisms including deletion and hypermethylation. We have investigated the deletion and methylation status of MTS1 and MTS2 in childhood acute lymphoblastic leukemia (ALL) of both T-cell (17 cases) and B-cell phenotypes (29 cases), and p16INK4A and p15INK4B mRNA expression in 36 of these cases. Biallelic or monoallelic loss of both MTS1 and MTS2 was observed in 12 cases of B-ALL and nine cases of T-ALL. Two cases of T-ALL showed deletion of MTS1 but not MTS2. The 5' CpG region of MTS2 was hypermethylated in 12 cases of precursor B-ALL and eight cases of T-ALL but no hypermethylation was found in the 5' CpG region of MTS1. All cases with homozygous deletion of MTS1 or MTS2 had no or low levels of mRNA expression and similar low levels of expression were found in cases in which MTS2 was present but fully methylated. Thus hypermethylation of MTS2, in contrast to MTS1, is frequent in childhood ALL. Furthermore our data show that although inactivation of MTS1 by deletion is common, inactivation of MTS2 by a combination of deletion and hypermethylation is more frequent in both B-ALL (20/29, 69%) and T-ALL (17/17, 100%). This suggests that both MTS1 and MTS2 are important targets of the 9p21-22 deletion.
Iravani
M
M
Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
Dhat
R
R
Price
C M
CM
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002648:Child; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008745:Methylation; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins