Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumor suppressor

SUMMARY Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three antiapoptotic BCL-2 proteins (MCL-1, BCL-2, and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Antiapoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in Suppressor of Fused (SUFU), a tumor suppressor and antagonist of the GLI DNA binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1, and BCL-XL. Antiapoptotic BCL-2 protein/SUFU feedforward signaling promotes cancer cell survival and growth and can be disabled with BH3 mimetics – small molecules that target antiapoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumors and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators

Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9Research in the context

Background: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/β-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear. Methods: We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs). Findings: We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/β-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML. Interpretation: By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins