Epigenetic analysis of childhood acute lymphoblastic leukemia

• DOI: 10.4161/epi.4.3.8752
• Publication Date: 2010-05-03T12:21:57Z
• Authors: Thomas L. Dunwell; Luke B. Hesson; Tatiana V. Pavlova; Veronika Zabarovska; Vladimir I. Kashuba; Daniel Catchpoole; Raffaella Chiaram...; Anna T. Brini; Mike Griffiths; Eamonn R. Maher; Eugene R. Zabarovsky; Farida Latif
• Keywords: 0301 basic medicine; Cancer Research; 0303 health sciences; Base Sequence; Gene Expression Regulation, Leukemic; Chromosome 3; Epigenetics; Gene expression; Leukaemia; NotI microarray; Gene Expression Profiling; Molecular Sequence Data; DNA Methylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Epigenesis, Genetic; 3. Good health; 03 medical and health sciences; Cell Line, Tumor; Humans; Chromosomes, Human, Pair 3; Gene Silencing; Molecular Biology; Oligonucleotide Array Sequence Analysis

We used a chromosome 3 wide NotI microarray for identification of epigenetically inactivated genes in childhood acute lymphoblastic leukemia (ALL). Three novel genes demonstrated frequent methylation in childhood ALL. PPP2R3A (protein phosphatase 2, regulatory subunit B", alpha) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, beta) showed frequent methylation in B-ALL (58%; 56% respectively), but were less frequently methylated in T-ALL (17% for both genes). Recently it was demonstrated that BNC1 (Basonuclin 1) and MSX1 (msh homeobox 1) were frequently methylated across common epithelial cancers. In our series of childhood ALL BNC1 was frequently methylated in both T (77%) and B-ALL (79%), whilst MSX1 showed T-ALL (25%) specific methylation. The methylation of the above five genes was cancer specific and expression of the genes could be restored in methylated leukemia cell lines treated with 5-aza-2'-deoxycytidine. This is the first report demonstrating frequent epigenetic inactivation of PPP2R3A, FBLN2, THRB, BNC1 and MSX1 in leukemia. The identification of frequently methylated genes showing cancer specific methylation will be useful in developing early cancer detection screens and for targeted epigenetic therapies.