Epigenetic analysis of childhood acute lymphoblastic leukemia

Abstract

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'', a) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, b) 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.

Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

“…Loss of FBLN2 expression was reported to be associated with cancer progression, although its functional role in tumor suppression has not been well characterized (Yi et al, 2007;Dunwell et al, 2009;Hill et al, 2010). Involvement of FBLN2 in NPC development was initially identified by its frequent deletion and methylation detected in the chromosome 3 genomic NotI microarray analysis of NPC cell lines in the present study.…”

“…Recent studies also reported the aberrant promoter hypermethylation of FBLN2 in childhood acute lymphoblastic leukemia, lung, colorectal and breast cancers (Dunwell et al, 2009;Hill et al, 2010). The significant downregulation and frequent promoter hypermethylation of FBLN2S further provides evidence for its involvement in NPC.…”

“…When tumor tissues were also screened to determine the extent of downregulation of these genes in clinical specimens, then all three genes showed over 46% downregulation (Table 1). As a result of the frequent methylation of FBLN2 detected in other cancers and its important roles in ECM (Dunwell et al, 2009;de Vega et al, 2009;Hill et al, 2010), it was chosen for further study.…”

“…The 591-bp putative FBLN2 CpG island in the promoter region mapping to position chr3:13565415-13566008 has been described (Supplementary Figure S1; Dunwell et al, 2009). The methylation status of FBLN2 was determined by bisulfite genomic sequencing and methylation-specific PCR.…”

“…Loss of FBLN2 protein expression is observed in breast cancer cell lines and tumors (Yi et al, 2007). Frequent FBLN2 methylation was detected in childhood acute lymphoblastic leukemia (Dunwell et al, 2009). Epigenetic studies showed FBLN2 is frequently methylated in breast, colorectal and lung cancers (Hill et al, 2010).…”