DNA methylation dynamic of bone marrow hematopoietic stem cells after allogeneic transplantation

Stem Cell Research & Therapy

Luigi Del Vecchio¹  Vittorio Simeon²  Angelo Michele Carella³  Lucia Savino³  Domenico Memoli⁴  Alessandro Weisz⁴  Francesco La Rocca⁵  Stefania Trino⁶  Luciana De Luca⁶  Giovanni Calice⁶  Pietro Zoppoli⁶  Ilaria Laurenzana⁶  Antonella Caivano⁶  Pellegrino Musto⁷ 

[1] 0000 0001 0790 385X, grid.4691.a, Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80138, Naples, Italy;0000 0001 2200 8888, grid.9841.4, Medical Statistics Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy;0000 0004 1757 9135, grid.413503.0, SSD Unità di terapia intensiva ematologica e terapie cellulari, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;0000 0004 1937 0335, grid.11780.3f, Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Baronissi, SA, Italy;Laboratory of Clinical Research and Advanced Diagnostics, IRCCS - Referral Cancer Center of Basilicata (CROB), 85028, Rionero in Vulture, Italy;Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), 85028, Rionero in Vulture, Italy;Unit of Hematology and Stem Cell Transplantation, IRCCS - Referral Cancer Center of Basilicata (CROB), 85028, Rionero in Vulture, Italy;

关键词: Allogeneic hematopoietic bone marrow stem cell transplantation;    Hematopoietic stem and progenitor cells;    DNA methylation;    CpG sites;    Hematological malignancies;    Promoter methylation region;   

DOI  :  10.1186/s13287-019-1245-6

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY