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Dysregulation of Immune Pathways in AML Relapse After Allogeneic HSCT

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Key Points

  • No relapse-specific mutations in immune-related genes were observed in relapse after transplantation.
  • Epigenetic changes included down-regulation of MHC class II genes involved in adaptive and innate immunity.

In a study reported in The New England Journal of Medicine, Christopher et al found that acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) was accompanied by dysregulation of immune pathways, including downregulation of major histocompatibility complex (MHC) class II genes, rather than relapse-specific mutations in immune-related genes.

Study Details

In the study, enhanced exome sequencing was performed in paired samples from initial presentation with AML and at relapse in 15 patients with relapse after transplantation. Transplants came from HLA-matched related donors, HLA-matched unrelated donors, or HLA-mismatched unrelated donors. Exome sequencing was also performed in paired samples from 20 patients with relapse after receiving chemotherapy. RNA sequencing and flow cytometry were performed on a subgroup of these samples and on samples from additional patients with relapse after transplantation for validation.

Mutation Findings

On exome sequencing, more than 250 genes were mutated exclusively in patients with a post-transplantation relapse, but only 2 genes (ETV6 and FAM98B) were mutated in more than one patient (each in 2 patients); this finding indicates absence of common driver mutations in relapse after transplantation. Overall, the recurrent mutations identified at relapse after transplantation were similar to those found in initial presentation samples and in samples from patients with relapse after chemotherapy, with no relapse-specific mutational patterns being identified.

Downregulation of MHC Class II Genes

Since mutations in known immune-related genes were not observed in AML relapse after transplantation, the investigators hypothesized that epigenetic changes in AML cells could play a role in relapse. RNA sequencing of the samples from patients with relapse after transplantation showed dysregulation of pathways involved in adaptive and innate immunity. This finding included downregulation of major histocompatibility complex (MHC) class II genes, including HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1, to levels 3 to 12 times lower than those observed in the paired baseline samples. Decreased expression of MHC class II protein at relapse was confirmed by flow cytometry and immunohistochemical analysis in 17 of 34 patients with relapse after transplantation. As noted by the investigators, there is evidence to suggest that interferon-γ treatment could act to reverse this phenotype in AML blasts.

The investigators concluded, “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 downregulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy.”

The study was funded by the National Cancer Institute, Leukemia and Lymphoma Society, and others.

Disclosures: See study authors’ full disclosures at nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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