Following allogeneic hematopoietic cell transplantation (allo-HCT), patients with acute myeloid leukemia (AML) frequently experience remission; however, they eventually pass away due to relapse caused by leukemia cells that are resistant to being destroyed by allogeneic T cells due to decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. For a study, researchers showed that blocking mouse-double-minute-2 (MDM2) can prevent AML from evading the immune system.

MHC class I and II expression was enhanced in murine and human AML cells by MDM2 suppression. They demonstrated that MDM2 suppression increased cytotoxicity against leukemia cells and improved survival using xenografts of human AML and syngeneic animal leukemia models. As a result of MDM2 inhibition, leukemia cells expressed higher levels of TRAIL-R1/2 (tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2), as well as more CD8+CD27lowPD-1lowTIM-3low T cells with characteristics of cytotoxicity (perforin+CD107a+TRAIL+) & longevity (bcl-2+IL-7R+). When compared to vehicle-control participants, CD8+ T cells from leukemia-carrying MDM2 inhibitor-treated allo-HCT recipients had greater glycolytic activity and enrichment for nucleotides and their precursors.

Leukemia was wiped out in secondary AML-bearing recipients by T cells derived from MDM2 inhibitor-treated AML-bearing mice. The effects of MDM2 inhibitors were p53-dependent since p53 knockdown prevented the overexpression of TRAIL-R1/2 and MHC-II while increasing p53 binding to TRAILR1/2 promoters. Data collected from human subjects were used to supplement the observations made in the mouse models. On MDM2 inhibition, patient-derived AML cells expressed more TRAIL-R1/2 and MHC-II.

In conclusion, by restoring p53-dependent TRAIL-R1/2 and MHC-II synthesis via MDM2 suppression AML cells to allogeneic T-cell-mediated cytotoxicity.

Reference: ashpublications.org/blood/article-abstract/140/10/1167/485955/Targeting-MDM2-enhances-antileukemia-immunity?redirectedFrom=fulltext