Promoter methylation and expression levels of selected hematopoietic genes in pediatric B-cell acute lymphoblastic leukemia

Abstract

BackgroundPrecursor B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common neoplasm in children and is characterized by genetic and epigenetic aberrations in hematopoietic transcription factor (TF) genes. This study evaluated promoter DNA methylation and aberrant expression levels of early- and late-acting hematopoietic TF genes homeobox A4 and A5 (HOXA4 and HOXA5), Meis homeobox 1 (MEIS1), T-cell acute lymphocytic leukemia 1 (TAL1), and interferon regulatory factors 4 and 8 (IRF4 and IRF8) in pediatric B-cell ALL.MethodsBlood samples of 38 ALL patients and 20 controls were obtained. DNA was treated with sodium bisulfite and DNA methylation level of HOXA4, HOXA5, MEIS1, TAL1, IRF4, and IRF8 was assessed using quantitative methylation-specific polymerase chain reaction (PCR). Relative gene expression was measured using quantitative reverse transcription-PCR.ResultsAberrant methylation of TAL1, IRF8, MEIS1, and IRF4 was observed in 26.3%, 7.9%, 5.3%, and 2.6% patients, respectively, but not in controls. HOXA4 and HOXA5 were methylated in some controls and hypermethylated in 16% and 5% patients, respectively. IRF8, MEIS1, and TAL1 expression was lower in patients than in controls. MEIS1 expression was inversely correlated with white blood cell (WBC) count. HOXA4 expression was down-regulated in patients with high risk according to the National Cancer Institute (NCI) classification. TAL1 methylation was slightly elevated in patients aged >9 years and in patients showing relapse, suggesting its potential prognostic value.ConclusionAberrant methylation and expression of the selected hematopoietic genes were correlated with demographic/clinical prognostic factors of pediatric ALL, such as age, WBC count, and NCI risk classification.

A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia

“…Thus, TAL1 promoter methylation may result in impaired hematopoietic differentiation and contribute to leukemogenic transformation and prognosis of leukemia. Indeed, a comparison of the methylation levels between cases who developed ALL relapse (n = 7) and those who did not (n = 31) showed a slight increase in the TAL1 promoter methylation level for relapse patients (median value 1.693 vs. 0%, p = 0.0129) [21] . However, the prognostic value of TAL1 hypermethylation in ALL needs to be validated in a larger number of patients, possibly using different DNA methylation techniques.…”

“…These studies suggest that changes in promoter methylation may be associated with relapse. The top methylated genes identified so far are T-cell acute lymphocytic leukemia 1 (TAL1) [21] , endogenous retrovirus group H, member 3 (ERHV-3) [22] , cyclin-dependent kinase inhibitor 2A (CDKN2A) [23] , CALCA [24,25] , and p15 [26,27] .…”

Aberrant DNA methylation-induced gene inactivation is associated with the diagnosis and/or therapy of T-cell leukemias

“…In the context of hematologic malignancies, DNMT overexpression has been observed in samples from leukemia patients [27]. These previous findings collectively suggest that dysregulated DNA hypermethylation may lead to gene silencing, thereby triggering leukemogenesis [28,29].…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…MEIS1 and HOXA4 expression and TAL1 methylation are correlated with WBC count, National Cancer Institute (NCI) risk classification and age, respectively. MEIS1 expression is inversely associated with WBC count, HOXA4 expression is down-regulated in patients with high risk based on the NCI classification and TAL1 methylation is rather increased in patients older than 9 years and in patients who show relapse (129). It has also been demonstrated that increased histone H4 acetylation is significantly associated with favorable RFS, EFS, OS in pediatric BCP-ALL (130).…”