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Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Purpose:The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT.Experimental Design:This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity.Results:We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus.Conclusions:Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Supplementary Data

Supplementary Figures 1-2 from CD8+ T cells Reactive to Survivin Antigen in Patients with Multiple Myeloma

Purpose: Survivin is a member of the inhibitors of apoptosis family and is overexpressed in different types of malignancies. Cytotoxic T cells recognizing survivin epitopes can be elicited in vitro and by vaccination in patients with leukemia, breast cancer, and melanoma. We did this study to investigate whether survivin-specific CD8+ T cells occur in patients with multiple myeloma.Experimental Design: An HLA-A2.1–binding survivin peptide was used to detect peptide-specific T cells by a quantitative real-time PCR to measure antigen-specific IFN-γ mRNA expression in 23 patients with myeloma and 21 healthy volunteers. T cells producing IFN-γ in response to survivin were further analyzed for expression of CD45RA and CCR7 to determine phenotypic characterization. Additional immunohistochemical analyses of survivin antigen expression in bone marrow specimens of patients was done.Results: T cells recognizing HLA-A2.1–binding survivin peptide were detected in 9 of 23 patients and in 1 of 21 healthy volunteers. Survivin-reactive T cells were identified as terminally differentiated effector T cells (CD8+, CD45RA+, and CCR7−). Positive survivin expression of myeloma cells in bone marrow specimens was shown in 7 of 11 patients.Conclusion: We provide, for the first time, evidence of T cell reactivity against survivin antigen in patients with multiple myeloma. Our data suggest the immunogenicity of survivin antigen in multiple myeloma and that immunotherapeutic strategies using survivin as a target antigen might be an option for patients with this disease.

TrackCHIP Mono YY1 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

Supplementary Table 1 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackCHIP THP1vsMono from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackCHIP U937vsMono from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

Supplementary Materials and Methods, Figures 1-7 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackCHIP Mono Sp1 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

Supplementary Table 2 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackEpityper Data Mono from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackEpityper Data U937 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackCHIP Mono NRF1 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

Supplementary Table 4 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

Supplementary Table 3 from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells

TrackEpityper Amplicons from General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells