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

Abstract

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. image Chromatin regulators play a crucial role in cancer, including acute myeloid leukemia (AML). Here, a screen for new vulnerabilities in MLL‐rearranged AML identifies an alternative NURF chromatin remodelling complex that maintains leukemic transcriptional programs. CRISPRi screen in AML cells identifies BPTF as an essential regulator of cell growth. BPTF interacts with SMARCA5 and BAP18 to form an alternative NURF complex in AML cells. The NURF complex controls insulator accessibility, CTCF binding, and TAD boundary formation. PHD2 and BROMO domains of BPTF are not required for leukemic cell growth.