Transcriptional plasticity drives leukemia immune escape

Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation (alloSCT) has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHC-II) proteins through unknown mechanisms. We developed CORENODE, a computational algorithm for genome-wide transcription network decomposition, that identified the transcription factors (TFs) IRF8 and MEF2C as positive regulators and MYB and MEIS1 as negative regulators of MHC-II expression in AML cells. We show that reduced MHC-II expression at relapse is transcriptionally driven by combinatorial changes in the levels of these TFs, acting both independently and through the MHC-II coactivator CIITA. Beyond the MHC-II genes, MYB and IRF8 antagonistically regulate a broad genetic program responsible for cytokine signaling and T-cell stimulation that displays reduced expression at relapse. A small number of cells with altered TF levels and silenced MHC-II expression are present at the time of initial leukemia diagnosis, likely contributing to eventual relapse. Our findings reveal an adaptive transcriptional mechanism of AML evolution after allogenic transplantation whereby combinatorial fluctuations of TF levels under immune pressure result in selection of cells with a silenced T-cell stimulation program.