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AML cells

New research suggests relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplant (HSCT) is related to changes in immune-related gene expression that may be reversible.

Researchers observed downregulation of major histocompatibility complex (MHC) class II genes in samples from patients who relapsed after HSCT.

However, interferon-gamma “rapidly reversed this phenotype” in vitro, according to the researchers.

Matthew J. Christopher, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, and his colleagues reported these findings in The New England Journal of Medicine.

The researchers set out to determine how genetic and epigenetic changes after HSCT may allow leukemic cells to avoid the graft-vs-leukemia effect and to see whether immune-related genes are affected by HSCT.

The team analyzed paired samples obtained at diagnosis and relapse from 15 AML patients who relapsed after HSCT and 20 AML patients who relapsed after chemotherapy. The team also analyzed additional samples from patients who relapsed after HSCT to validate initial findings.

Methods of analysis included enhanced exome sequencing, RNA sequencing, flow cytometry, and immunohistochemical analysis.

Findings

The researchers first looked for relapse-specific mutations but found no driver mutations associated with relapse after HSCT.

The mutations seen post-HSCT relapse were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy, and the researchers could not identify any patterns of mutations related to relapse.

They then looked for, but did not find, relapse-specific mutations in genes involved in modulation of immune checkpoints, antigen presentation, or cytokine signaling.

The researchers did, however, find evidence of epigenetic changes that were more common in the samples from patients with post-transplant relapses.

RNA sequencing showed that MHC class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) were downregulated three- to 12-fold after transplant.

Flow cytometry and immunohistochemical analysis confirmed that MHC class II expression was decreased at relapse after HSCT in 17 of 34 samples evaluated.

The researchers said there was no association between the downregulation of MHC class II and donor type or use of immunosuppression.

To see whether the downregulation of MHC class II genes was reversible, the researchers treated three post-HSCT relapse samples with interferon-gamma, which is known to upregulate MHC class II on certain cells.

Culturing patient cells with interferon-gamma “rapidly induced MHC class II protein expression on leukemic blasts,” the researchers said. They observed “essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours.”

This study was supported by the National Institutes of Health, Leukemia and Lymphoma Society, and the Barnes-Jewish Hospital Foundation.

Several study authors reported personal fees and/or research support from industry outside the submitted work.


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