An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Efficient treatment of acute myeloid leukemia (AML) patients remains a challenge despite recent therapeutic advances. Here, using a CRISPRi screen targeting chromatin factors, we identified the nucleosome-remodeling factor (NURF) subunit 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 domains of BPTF, while contributing to complex recruitment to chromatin, 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.

Automated summary

This study identified the nucleosome-remodeling factor BPTF as a crucial regulator for the survival of AML cells. BPTF forms a complex with other proteins that remodels the chromatin structure in leukemia cells and maintains the normal gene expression program. The study also found that specific chromatin reader domains in BPTF are dispensable for the growth of leukemia cells.