Transcriptional Plasticity Drives Leukemia Immune Escape

Abstract

Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation 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 a transcription factor (TF) tetrad, consisting of IRF8, MYB, MEF2C and MEIS1, regulating MHC-II expression in AML cells. We show that reduced MHC-II expression at relapse is transcriptionally driven by combinatorial changes in the expression of these TFs, where MYB and IRF8 play major opposing roles, acting independently of the IFN-gamma/CIITA pathway. 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 abundance and silenced MHC-II expression are present at the time of initial leukemia diagnosis, likely contributing to eventual relapse.

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

“…4E ), consistent with their role as a lineage-determinant factor promoting monocytic differentiation 42 – 44 . Of the recently reported 19 core transcriptional regulators of lineage survival in AML 45 , 11 were predicted by SCENIC, all of which demonstrated significant differences in regulon activity across cytogenetic groups (Fig. 3E ).…”

Leukemia core transcriptional circuitry is a sparsely interconnected hierarchy stabilized by incoherent feed-forward loops

“…Dynamic rewiring of gene regulatory networks underpins normal development, malignant transformation, and tumor evolution (6,11,17,19,39,(54)(55)(56)(57)(58)(59). Orchestration of precise gene expression programs in a developing tissue while responding to environmental cues requires a gene regulatory network to balance robustness with plasticity (60).…”

Rapid-kinetics degron benchmarking reveals off-target activities and mixed agonism-antagonism of MYB inhibitors

“…MYB is a critical transcriptional dependency of acute myeloid leukemia (AML) 11,18,28,29 , where it has been a longterm focus of therapeutic efforts [30][31][32][33][34][35][36][37] , making AML a relevant context for functional characterization of MYB inhibitors. We therefore began by engineering a chemical degron model of MYB in AML cells.…”