Synergistic targeting of mSWI/SNF and UTX reveals a novel combination therapy in T-cell acute lymphoblastic leukemia

Dysregulated expression of oncogenic transcription factors (TFs) is a critical hallmark of T-cell acute lymphoblastic leukemia (T-ALL). These aberrations disrupt the tightly regulated spatial-temporal expression of downstream target genes and rewire transcriptional programs, culminating in a state of “transcription addiction”. We show that oncogenic factors such as RUNX1 and NOTCH1 in T-ALL recruit the mSWI/SNF chromatin-remodeling complex to modulate chromatin accessibility at target gene loci to initiate and maintain oncogenic transcriptional networks. Inhibiting mSWI/SNF function with SMARCA2/4 ATPase inhibitors (FHD-286) or PROTAC degraders (ACBI-1) targeting the SMARCA protein induces apoptosis and impairs T-ALL cell growth. To further dissect the functional dependencies of T-ALL cells on the mSWI/SNF complex, we performed genome-wide CRISPR knockout (KO) screens in T-ALL cells treated with FHD-286 or ACBI-1. These screens revealed that multiple members of the Mediator complex were high-confidence targets whose individual knockout was sufficient to rescue T-ALL cells from inhibitor-induced cell death. In contrast, knockout of the histone demethylase UTX sensitized T-ALL cells to mSWI/SNF inhibition. Notably, the IC50 of FHD-286 treatment decreased significantly in UTX KO cells compared to wild-type (WT) controls. Furthermore, UTX KO T-ALL xenograft mice showed improved survival when treated with FHD-286 compared to FHD-286-treated WT xenografts. A synergistic effect emerged when T-ALL cells or patient-derived xenografts (PDXs) were co-treated with GSK-J4, a histone demethylase inhibitor, and FHD-286. Transcriptomic analyses indicated that genes promoting ribosomal and mitochondrial function were substantially downregulated in UTX KO T-ALL cells treated with FHD-286 but not in similarly treated WT cells, suggesting a previously unrecognized role of UTX in gene regulation. Overall, these findings demonstrate that simultaneously targeting the mSWI/SNF complex and UTX may represent an innovative combinatorial strategy for T-ALL treatment.