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