CPSF6-RARγ Interacts with HDAC3 to Promote Myeloid Transformation [CUT&Tag in CD34+ cells]

Acute myeloid leukemia (AML) with RARG fusions, which clinic features resemble acute promyelocytic leukemia (APL), have been identified as a new subtype with poor clinical outcomes. The underlying mechanism of RARG fusion is poorly understood, which needs to be explored urgently to develop effective therapeutic strategies. Using hematopoietic specific knock-in mouse model and xenograft mouse model transplanted with oncogene transduced human CD34+ cells, we revealed that CPSF6-RARG (CR) fusion, one of the most prevalent recurrent RARG translocations, enhances expansion of immature cells and impairs myeloid maturation, synergizing with RAS mutation to drive more aggressive myeloid malignancies. Mechanistically, CR recruits the histone deacetylase 3 (HDAC3) to suppress the transcription of PU.1, a key transcription factor for myeloid lineage specification. CR driven leukemia is more sensitive to HDAC inhibitors in vitro and in vivo. Hence, our data reveals the molecular bases of the oncogenic CR fusion and provides a potential targeted therapeutic approach against AML with CR fusions.