Impact of Epigenomic Hypermethylation at TP53 on Allogeneic Hematopoietic Cell Transplantation Outcomes for Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic cell transplantation (HCT) is currently the sole curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, and in MDS, epigenetic-based interventions have emerged as life-prolonging therapies. However, the impact of epigenomic aberrations on HCT outcomes among patients with MDS are not well understood. We hypothesized that epigenomic signatures in MDS patients before undergoing HCT serve as a novel prognostic indicator of the risk of post-HCT MDS relapse. To evaluate these epigenomic signatures in MDS patients, we analyzed reduced representation bisulfite sequencing profiles in a matched case-control population of 94 patients. Among these HCT recipients, 47 patients with MDS who relapsed post-HCT (cases) were matched 1:1 to patients with MDS who did not relapse (controls). Only patients with wild-type TP53, RAS pathway, and JAK2 mutations were included in this study to promote the discovery of novel factors. Cases were matched with controls based on conditioning regimen intensity, age, sex, Revised International Prognostic Scoring System, Karnofsky Performance Status, graft type, and donor type. Pre-HCT whole-blood samples from cases and matched controls were obtained from the Center for International Blood and Marrow Transplant Research repository. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns among matched cases and controls. Our findings show that cases displayed more hyper-DMRs pretransplantation compared with controls, even after adjusting for pre-HCT use of hypomethylating agents. Hyper-DMRs specific to cases were mapped to the transcription start site of 218 unique genes enriched in 5 different signaling pathways that may serve as regions of interest and factors to consider as prognostic determinants of post-HCT relapse in MDS patients. Interestingly, although patients selected for this cohort were wild-type for the TP53 gene, cases showed significantly greater levels of methylation at TP53 compared with controls. These findings indicate that previously identified prognostic genes for MDS, such as TP53, may affect disease relapse not only through genetic mutation, but also through epigenetic methylation mechanisms.

Keywords: DNA methylation; Epigenomics; Hematopoietic cell transplantation; Myelodysplastic syndromes; TP53; Transplantation outcome.

Figure 1.

Distribution of DMRs in cases (relapsed) and controls (nonrelapsed). (A) There were more regions of hypermethylation in cases compared with controls than in the reverse direction. (B) Total number of differentially methylated cytosines by genomic features, with the ratio of hypermethylation in cases versus controls in dark gray and vice versa in light yellow. DMRs were enriched in promoters.

Figure 2.

Significantly more hypermethylated cytosines compared with hypomethylated cytosines were detected in the transcription start site of TP53 in cases (relapsed) versus controls (nonrelapsed). (A) DMRs near TP53 with exons numbered where hypermethylated regions are shown above the horizontal line, and hypomethylated regions appear below the line. (B) Differentially methylated regions by genomic feature near TP53 (hypermethylated shown in dark gray, hypomethylated in light gray). (C) As in (B) but considering only patients treated with HMA.

Figure 3.

Transplantation outcomes in MDS patients may be determined by the presence of genetic mutations or epigenetic hypermethylation in key prognostic genes, such as TP53. In scenario (1), patients with the wild-type TP53 gene at wild-type methylation levels pretransplantation do not experience relapse post-transplantation. However, those patients with (2) genetic mutations at TP53 or (3) hypermethylation at TP53 pretransplantation are at increased risk of MDS disease relapse post-transplantation.