DNA methylation and copy number variation profiling of T-cell lymphoblastic leukemia and lymphoma

Zahra Haider,Jukka Kanerva,Mattias Landfors,Sofie Degerman,Trond Flægstad,Martin Erlanson,Irina Golovleva,Kjeld Schmiegelow,Ulrika Norén-Nyström,Magnus Hultdin

doi:10.1038/s41408-020-0310-9

Abstract

Despite having common overlapping immunophenotypic and morphological features, T-cell lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) have distinct clinical manifestations, which may represent separate diseases. We investigated and compared the epigenetic and genetic landscape of adult and pediatric T-ALL (n = 77) and T-LBL (n = 15) patient samples by high-resolution genome-wide DNA methylation and Copy Number Variation (CNV) BeadChip arrays. DNA methylation profiling identified the presence of CpG island methylator phenotype (CIMP) subgroups within both pediatric and adult T-LBL and T-ALL. An epigenetic signature of 128 differentially methylated CpG sites was identified, that clustered T-LBL and T-ALL separately. The most significant differentially methylated gene loci included the SGCE/PEG10 shared promoter region, previously implicated in lymphoid malignancies. CNV analysis confirmed overlapping recurrent aberrations between T-ALL and T-LBL, including 9p21.3 (CDKN2A/CDKN2B) deletions. A significantly higher frequency of chromosome 13q14.2 deletions was identified in T-LBL samples (36% in T-LBL vs. 0% in T-ALL). This deletion, encompassing the RB1, MIR15A and MIR16-1 gene loci, has been reported as a recurrent deletion in B-cell malignancies. Our study reveals epigenetic and genetic markers that can distinguish between T-LBL and T-ALL, and deepen the understanding of the biology underlying the diverse disease localization.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are precursor lymphoid neoplasms, characterized by the uncontrolled proliferation of progenitor T-cells
There were no significant differences in age and gender distribution between T-ALL and T-LBL patients, and both malignancies showed higher prevalence in males (Table 1)
Genome-wide DNA methylation profiling Genome-wide DNA methylation patterns across adult and pediatric T-ALL and T-LBL patient samples along with reference samples were explored by principal component analysis (PCA) analysis on batch-effect corrected DNA methylation array data (Fig. 1, Supplementary Fig. S2)

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are precursor lymphoid neoplasms, characterized by the uncontrolled proliferation of progenitor T-cells. A lymphoid neoplasm with a bone marrow infiltration of malignant blast cells by more than 20–25% is classified as T-ALL1. If the bone marrow infiltration is less than 25% and the primary disease localizes in the mediastinum, lymph nodes or the extramedullary tissues, it is classified as T-LBL1. Despite differences in clinical manifestation, T-ALL and T-LBL have an overlapping immunophenotype and recurrent island methylator phenotype (CIMP) panel, consisting of 1293 specific CpG sites, which classified pediatric T-ALL patients into clinically relevant subgroups[6,7]. (low methylation) T-ALL patient subgroup had a significantly worse prognosis compared to the CIMP+ (high methylation) subgroup[6,7,9].

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