An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions.
Aliaksandra RadzisheuskayaIsabel Peña-RømerEugenia LorenziniRichard KocheYingqian ZhanPavel V ShliahaAlexandra J CooperZheng FanDaria ShlyuevaJens V JohansenRonald C HendricksonKristian HelinPublished in: The EMBO journal (2023)
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.
Keyphrases
- acute myeloid leukemia
- transcription factor
- gene expression
- allogeneic hematopoietic stem cell transplantation
- dna damage
- genome wide
- end stage renal disease
- ejection fraction
- induced apoptosis
- chronic kidney disease
- cancer therapy
- prognostic factors
- cell death
- patient reported outcomes
- binding protein
- bone marrow
- acute lymphoblastic leukemia
- heat shock protein