DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T‐Cell Acute Lymphoblastic Leukemia

Abstract

Background Despite increased knowledge about genetic aberrations in pediatric T‐cell acute lymphoblastic leukemia (T‐ALL), no clinically feasible treatment‐stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T‐ALL. Procedure Sixty‐five diagnostic T‐ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T‐cell precursor (ETP) phenotype. Results Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP‐negative profile had an inferior response to treatment compared to CIMP‐positive patients (3‐year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high‐risk T‐ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP‐negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP‐positive group. Conclusions CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

Pediatric T‐cell acute lymphoblastic leukemia

“…This has, however, not been seen in all studies and, furthermore, these studies were based on quite a low number of patients, which often included both pediatric and adult patients, precluding any firm conclusions as to the prognostic role of miRs in childhood T‐ALL (Kaddar et al, ; Gimenes‐Teixeira et al, ; Xi et al, ). Data on promoters that are differentially methylated in T‐ALL have been applied to define CpG island methylator phenotypes, delineating cases as either hypermethylated or hypomethylated (Borssén et al, ), with hypomethylated cases having a significantly worse event‐free and overall survival in one of the studies (Borssén et al, ). Obviously, this needs to be addressed in larger, prospective cohorts.…”

An integrated transcriptome analysis in T‐cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression

“…DNA methylation alterations have been associated with prognosis in various hematological disorders . We have previously shown, in two independent cohorts, prognostically relevant subgrouping of pediatric T‐ALL samples at diagnosis based on a CIMP (CpG island methylator phenotype) panel including 1293 gene promoter enriched CpG sites . In both cohorts, the CIMP− subgroup, with a methylation profile closer to normal T cells, had a worse prognosis than the CIMP+ subgroup (36% vs 86% 5‐year event‐free survival in the NOPHO ALL 1992/2000 treated cohort and 29% vs 6% 3‐year cumulative incidence of relapse in the NOPHO ALL 2008 treated cohort) .…”

“…We have previously shown, in two independent cohorts, prognostically relevant subgrouping of pediatric T‐ALL samples at diagnosis based on a CIMP (CpG island methylator phenotype) panel including 1293 gene promoter enriched CpG sites . In both cohorts, the CIMP− subgroup, with a methylation profile closer to normal T cells, had a worse prognosis than the CIMP+ subgroup (36% vs 86% 5‐year event‐free survival in the NOPHO ALL 1992/2000 treated cohort and 29% vs 6% 3‐year cumulative incidence of relapse in the NOPHO ALL 2008 treated cohort) . The prognostic relevance was further strengthened in the NOPHO ALL 2008 treated cohort by combining CIMP status with minimal residual disease (MRD) status at the end of the induction therapy, which allowed subgrouping of high‐risk T‐ALL patients (MRD > 0.1% at day 29) (3‐year cumulative incidence of relapse in the MRD > 0.1%/CIMP− subgroup was 50% vs 12% in the MRD>0.1%/CIMP+ subgroup) …”

Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature

“…On the other hand, various studies have shown an important role of epigenetic aberrations in the pathogenesis of pediatric acute leukemia, including T-ALL, and resistance to chemotherapy [6]. In particular, Borssen et al recently showed that the amount of CpG island methylation could predict the outcome and response to standard treatment [7]. …”