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Item Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers(CSH Press, 2021-12) Mikulasova, Aneta; Kent, Daniel; Trevisan-Herraz, Marco; Karataraki, Nefeli; Fung, Kent T. M.; Ashby, Cody; Cieslak, Agata; Yaccoby, Shmuel; Rhee, Frits van; Zangari, Maurizio; Thanendrarajan, Sharmilan; Schinke, Carolina; Morgan, Gareth J.; Asnafi, Vahid; Spicuglia, Salvatore; Brackley, Chris A.; Corcoran, Anne E.; Hambleton, Sophie; Walker, Brian A.; Rico, Daniel; Russell, Lisa J.; Medicine, School of MedicineChromosomal translocations are important drivers of hematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B cell (MAF, MYC and FGFR3/NSD2) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.Item Pretransplant HLA typing revealed loss of heterozygosity in the major histocompatibility complex in a patient with acute myeloid leukemia(Elsevier, 2019) Lobashevsky, Andrew L.; Krueger-Sersen, Mary; Britton, Rebecca M.; Littrell, Courtney A.; Singh, Susmita; Cui, Connie P.; Kashi, Zahra; Martin, Russ K.; Breman, Amy M.; Vance, Gail H.; Farag, Sherif S.; Medicine, School of MedicineIntroduction Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. Purpose of the study In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. Materials and methods HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. Results Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. Conclusions LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.