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Allogeneic hematopoietic stem cell transplantation (HSCT), a consolidation therapy strategy in acute myeloid leukemia (AML), is thought to act via an immune-mediated graft-versus-leukemia (GvL) effect. A group of researchers from the McDonnell Genome Institute, Washington, US, hypothesized that immune-mediated mechanisms induced by allogeneic HSCT may cause distinct patterns of tumor evolution in relapsed AML. This theory was investigated and the results of the study were published in the New England Journal of Medicine.
In order to identify genetic and epigenetic alterations that allow leukemia cells to escape the GvL effect, the researchers performed a comprehensive analysis of samples from patients who had relapse of AML after transplantation. Exome sequencing was performed on paired samples obtained from 15 patients at initial presentation and relapse after allogeneic HSCT. For comparison, samples from 20 patients who had relapse after chemotherapy alone were also analyzed.
In order to investigate whether epigenetic changes might be contributing to disease evolution post-transplant, total RNA sequencing was performed on enriched AML blasts from paired samples from seven patients at initial presentation and at post-transplant relapse. Samples from nine patients who relapsed after chemotherapy were also analyzed.
To determine the prevalence of the down-regulation of MHC class II genes, 10 additional patients with post-transplant relapse were analyzed using flow cytometry, yielding a total of 16 patients with post-transplant relapse.
Furthermore, single-cell RNA sequencing in one patient with post-transplant relapse revealed a high expression of MHC class II genes in the vast majority of AML cells at presentation. In addition, no subclone with low MHC class II genes was detected. This indicates, according to the researchers, that clones evolved in response to immune-mediated selective pressure and ultimately escape, thus leading to relapse.
In summary, AML cells at post-transplant relapse associated with a downregulated MHC class II gene expression, which allows the cells to escape immune detection which eventually leads to relapse. The researchers concluded by stating that “AML cells that escaped the immune surveillance provided by allogeneic T cells after allogeneic hematopoietic stem-cell transplantation frequently had dysregulation of a number of pathways that regulate immune function. These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible”.
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