期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 379, 期 24, 页码 2330-2341出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1808777
关键词
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资金
- National Cancer Institute (NCI) K12 Program grant [CA167540]
- NCI K08 Program [CA222630-01]
- Specialized Program of Research Excellence Career Development Award [CA171963]
- Leukemia and Lymphoma Society Scholar Award
- NCI Outstanding Investigator Award [R35 CA197561]
- Barnes-Jewish Hospital Foundation [00335-0505-02]
- NCI Research Specialist Awards [R50 CA211466, R50 CA211782]
- Genomics of Acute Myeloid Leukemia Program Project grant [P01 CA101937]
- Specialized Program of Research Excellence in Acute Myeloid Leukemia grant [P50 CA171963]
- NATIONAL CANCER INSTITUTE [K12CA167540, K08CA166229, P50CA171963, R50CA211782, R50CA211466, P01CA101937, R35CA210084, R35CA197561, K08CA222630] Funding Source: NIH RePORTER
BACKGROUND As consolidation therapy for acute myeloid leukemia (AML), allogeneic hematopoietic stem-cell transplantation provides a benefit in part by means of an immunemediated graft-versus-leukemia effect. We hypothesized that the immune-mediated selective pressure imposed by allogeneic transplantation may cause distinct patterns of tumor evolution in relapsed disease. METHODS We performed enhanced exome sequencing on paired samples obtained at initial presentation with AML and at relapse from 15 patients who had a relapse after hematopoietic stem-cell transplantation (with transplants from an HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor) and from 20 patients who had a relapse after chemotherapy. We performed RNA sequencing and flow cytometry on a subgroup of these samples and on additional samples for validation. RESULTS On exome sequencing, the spectrum of gained and lost mutations observed with relapse after transplantation was similar to the spectrum observed with relapse after chemotherapy. Specifically, relapse after transplantation was not associated with the acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes. In contrast, RNA sequencing of samples obtained at relapse after transplantation revealed dysregulation of pathways involved in adaptive and innate immunity, including down-regulation of major histocompatibility complex (MHC) class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) to levels that were 3 to 12 times lower than the levels seen in paired samples obtained at presentation. Flow cytometry and immunohistochemical analysis confirmed decreased expression of MHC class II at relapse in 17 of 34 patients who had a relapse after transplantation. Evidence suggested that interferon-gamma treatment could rapidly reverse this phenotype in AML blasts in vitro. CONCLUSIONS AML relapse after transplantation was not associated with the acquisition of relapse- specific mutations in immune-related genes. However, it was associated with dysregulation of pathways that may influence immune function, including down-regulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy.
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