The alternative Nucleosome Remodeling Factor complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions (Cut&Run)
Efficient treatment of Acute Myeloid Leukemia (AML) patients remains a challenge despite recent advances. Here using a CRISPRi screen targeting chromatin factors, we identified BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader modules of BPTF are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML. Overall design: 3 Cut&Run experiments. Experiment 1: BPTF genomic localization in wild type and BPTF KO cells. Experiment 2: HA-tagged SMARCA5 genomic localization in HA-SMARCA5-dTAG KI cell line treated with DMSO or with dTAG-V1. Experiment 3: BPTF genomic localization in wild type cells or in cells with BPTF truncations. 2 biological replicates were used for all the experiments. Experiment 4: CTCF Cut&Run in wild-type, BPTF KO and SMARCA5 KO THP-1 cells. The data for two indepdendent experiments is provided, the second experiment in 2 biological replicates. Experiment 5: CTCF, BPTF and SMARCA5 genomic profiling by Cut&Run in U937 and OCI-AML2 cells.