Relapse in Acute Myeloid Leukemia and Dysregulation of Immune Genetic Pathways

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One of the effects of immune pathway dysregulation was decreased antigen presentation by MHC Class II genes.
One of the effects of immune pathway dysregulation was decreased antigen presentation by MHC Class II genes.

Relapse in patients with acute myeloid leukemia (AML) who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) does not appear to be associated with relapse-specific mutations in genes related to immune responses. However, dysregulation of pathways that may influence immune function, including antigen presentation by major histocompatibility complex (MHC) class II genes, may be involved, according to reseearch published in the New England Journal of Medicine

Researchers analyzed DNA-sequencing data from AML cells collected from 15 patients who experienced relapse after receiving allogeneic HSCT. These patients were compared with 20 AML patients who experienced relapse after chemotherapy. The researchers found that the mutations that were present in relapsed AML cells of patients who underwent HSCT were similar to the mutations present in relapsed AML cells of patient who received chemotherapy. However, there were significant differences in the cells' patterns of gene expression. 

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The researchers found that recurrent mutations and structural variations were not detected in genes involved with immune function in AML cells from patients who experienced relapse post HSCT. The researchers also found no relapse-specific mutations in genes involved in antigen presentation, cytokine signaling, or immune checkpoint modulation in post-transplant relapse cases.

 Several post HSCT samples with low MHC class II expression failed to stimulate third party CD4+ T cells in vitro. The findings suggest it may be possible to resensitize patients with AML. “What surprised us is that in the cases we looked at, the loss of MHC expression was reversible. This raises the possibility that in the future we may be able to resensitize relapsed AML cells to the graft-vs-tumor effect,” Matthew J. Christopher, MD, PhD, assistant professor of medicine at Washington University School of Medicine in St. Louis, Missouri, said in an interview with Hematology Advisor.

He noted that it has long been recognized that stem cell transplants help prevent AML relapse, in part, through immune surveillance. Since the 1990s, research has shown that MHC expression can be lost in AML cells at relapse. In the current study, researchers used RNA sequencing and found dysregulation of pathways involved in adaptive and innate immunity, including genes required for MHC class II presentation.

The researchers used flow cytometry and immunohistochemistry to confirm low expression of MHC class II genes in 17 of 34 samples analyzed from patients who experienced relapse after transplant. They also demonstrated that in vitro interferon gamma treatment could rapidly reverse this phenotype of low expression in AML blasts. Currently, interferon gamma is approved by the US Food and Drug Administration for treating chronic granulomatous disease.

“Our findings suggest that AML cells that have downregulated MHC class II don't stimulate good immune responses from donor T cells in vitro. It might be that patients who have lost MHC class II expression on their AML cells will get less benefit from donor lymphocyte infusions after relapse, although this will certainly take more work to prove,” Dr Christopher said.

Reference

1. Christopher MJ, Petti AA, Rettig MP, et al. Immune escape of relapsed AML cells after allogeneic transplantation [published online October 31, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1808777

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