Pbrm1 regulates interferon signaling in mouse AML [ChIP-seq HAP1]

CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled genetic mutagenesis screen of epigenetic factors in primary murine HSPCs, we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled mutagenesis of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient AML cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of Pbrm1 in control of interferon pathway components and found that Pbrm1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates in MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has revealed a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for epigenetic factor Pbrm1/Baf180 in HAP1 cells without or with IFN-γ treatment.