R274X-mutated Phf6 increased the self-renewal and skewed T cell differentiation of hematopoietic stem cells.

The PHD finger protein 6 (PHF6) mutations frequently occurred in hematopoietic malignancies. Although the R274X mutation in PHF6 ) is one of the most common mutations identified in T cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients, the specific role of in hematopoiesis remains unexplored. Here, we engineered a knock-in mouse line with conditional expression of Phf6-mutated protein in the hematopoietic system ( mouse). The mice displayed an enlargement of hematopoietic stem cells (HSCs) compartment and increased proportion of T cells in bone marrow. More T cells were in activated status than control. Moreover, mutation led to enhanced self-renewal and biased T cells differentiation of HSCs as assessed by competitive transplantation assays. RNA-sequencing analysis confirmed that mutation altered the expression of key genes involved in HSC self-renewal and T cell activation. Our study demonstrated that plays a critical role in fine-tuning T cells and HSC homeostasis.