Abstract
BackgroundAllogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant.MethodsWe measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day + 30 (t1), + 60 (t2), + 120 (t3), + 180 (t4), and + 365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets.ResultsResults show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30 days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell “adaptation” in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30 days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL.ConclusionsOverall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes.
Highlights
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT
Analysis of global DNA methylation profile in both donor and recipient hematopoietic stem and progenitor cells (HSPCs) Global methylation profiles were investigated in bone marrow (BM) HPSCs purified as CD34+ cells from 10 donors (t0) and 10 respective HM recipients [3 acute lymphoid leukemia (ALL), 6 acute myeloid leukemia (AML), and 1 Hodgkin lymphoma (HL)] in sequential time points [30 (t1), 60 (t2), 120 (t3), 180 (t4), and 365 (t5) days] after AHSCT
EPIC probes are located at transcription start site (TSS) 1500, TSS 200, 5′ untranslated region (UTR), first exon, gene body, 3′UTR, exon boundaries, and intergenic regions
Summary
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. One important hallmark of the epigenome is its great plasticity in response to internal (i.e., during development and transplant) and environmental factors [3] This process is important for normal biological functions like immune cell development and differentiation [4] and for tumor conditions [3]. Methylation status of the majority of CpG islands across a variety of tissues and cell populations is non-dynamic and less variant [13,14,15]. Have shown that DNA methylation of shore and shelf in intergenic region was associated with increased gene expression [14, 16] and a hypo-methylation of open sea with a transcriptional silencing [17]
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