Patients with acute myeloid leukaemia (AML) can derive benefit from allogeneic stem cell transplantation, but many patients ultimately relapse. The results of a study led by Timothy Ley and John DiPersio now provide insights into a potentially actionable mechanism of relapse after transplantation.

In a cohort of 15 patients with disease relapse after transplantation and 20 patients with relapse after consolidation chemotherapy, “we first looked for mutations that could potentially provide a mechanism, but did not find any that were unique to post-transplantation relapses,” explains Ley. The authors then analysed AML cells from 7 patients with post-transplantation relapse and 9 patients with post-chemotherapy relapse using RNA sequencing. “We saw a big difference in the expression of a number of genes that are important in immune cell recognition and function — and most of these changes were restricted to the post-transplantation relapse samples,” Ley describes. In 6 of 7 patients with post-transplantation relapse, the expression of 4 major histocompatibility complex class II (MHCII) genes and of several genes involved in antigen processing and presentation by MHCII molecules was significantly downregulated. Flow cytometry and immunohistochemistry were used to confirm this downregulation at the protein level and to validate the result in samples from an additional 27 patients.

“We could rapidly reverse this change in AML blasts by treating them with IFNγ [known to upregulate MHCII expression in several cell types] in vitro, suggesting that the mechanism is epigenetic,” comments Ley. He adds: “downregulation of MHCII expression can easily be screened for in all patients with relapsed AML after transplantation. We are very interested in studying whether the administration of IFNγ (or an agonist of IFNγ signalling) could potentially resensitize the AML blasts of these patients — who have very limited therapeutic options — to the graft-versus-leukaemia effect that is essential for the success of allogeneic transplantation.”