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Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs. [Display omitted] • A positive selection genome-wide CRISPR-Cas9 screen identifies POU2F3 regulators • The mSWI/SNF complex maintains POU2F3 and its oncogenic program • Neuroendocrine (NE) status demarcates two subclasses of POU2F3+ SCLC • Non-NE POU2F3+ SCLCs are highly sensitive to SMARCA4/2 inhibitors and BRD9 degraders Duplaquet et al. use positive-selection CRISPR screening to identify that mSWI/SNF chromatin remodeler complexes regulate POU2F3 and its oncogenic program in SCLC and are required for POU2F3+ SCLC survival. Clinical-grade SMARCA4/2 inhibitors or BRD9 degraders demonstrate efficacy in POU2F3+ patient-derived and cell line xenograft models. [ABSTRACT FROM AUTHOR]

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability. [Display omitted] • mSWI/SNF complex and its ATPase subunit are epigenetic dependencies in SCLC-P • POU2F3 complex requires the mSWI/SNF complex to modulate chromatin accessibility • POU2AF1 and IRF4 function as an epigenetic complex requiring mSWI/SNF in MM • An oral mSWI/SNF ATPase degrader shows potent anti-tumor efficacy in SCLC-P and MM He et al. reveal a promising avenue of treatment for small cell lung cancer and multiple myeloma driven by POU2F/POU2AF. The study highlights the potential of targeting the mSWI/SNF complex to impede oncogenic POU2F/POU2AF signaling and tumor growth, offering hope for improved therapies in these aggressive cancer types. [ABSTRACT FROM AUTHOR]

Summary The Mixed Lineage Leukemia gene (MLL) is altered in leukemia by chromosomal translocations to produce oncoproteins composed of the MLL N-terminus fused to the C-terminus of a partner protein. Here, we used domain-focused CRISPR screening to identify ZFP64 as an essential transcription factor in MLL -rearranged leukemia. We show that the critical function of ZFP64 in leukemia is to maintain MLL expression via binding to the MLL promoter, which is the most enriched location of ZFP64 occupancy in the human genome. The specificity of ZFP64 for MLL is accounted for by an exceptional density of ZFP64 motifs embedded within the MLL promoter. These findings demonstrate how a sequence anomaly of an oncogene promoter can impose a transcriptional addiction in cancer. Graphical Abstract Highlights • A CRISPR screen identifies ZFP64 as selectively essential in MLL leukemia • The essential function of ZFP64 in leukemia is to maintain MLL expression • The MLL promoter is the most enriched location of ZFP64 in the human genome • ZFP64 motif dominance underlies its exceptional specificity for MLL regulation Lu et al. show that MLL -rearranged leukemia is addicted to the transcription factor ZFP64 due to direct regulation of MLL by ZFP64. The MLL promoter has an unusually high number of ZFP64 binding motifs and is the most enriched location of ZFP64 occupancy in the human genome. [ABSTRACT FROM AUTHOR]

Summary RING-between-RING (RBR) E3s contain RING1 domains that are structurally similar yet mechanistically distinct from canonical RING domains. Both types of E3 bind E2∼ubiquitin (E2∼Ub) via their RINGs but canonical RING E3s promote closed E2∼Ub conformations required for direct Ub transfer from the E2 to substrate, while RBR RING1s promote open E2∼Ub to favor Ub transfer to the E3 active site. This different RING/E2∼Ub conformation determines its direct target, which for canonical RING E3s is typically a substrate or substrate-linked Ub, but is the E3 active-site cysteine in the case of RBR-type E3s. Here we show that a short extension of HHARI RING1, namely Zn 2+ -loop II, not present in any RING E3s, acts as a steric wedge to disrupt closed E2∼Ub, providing a structural explanation for the distinctive RING1-dependent conformational restriction mechanism utilized by RBR E3s. [ABSTRACT FROM AUTHOR]