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

Abstract

The PHD finger protein 6 (PHF6) mutations frequently occurred in hematopoietic malignancies. Although the R274X mutation in PHF6 (PHF6R274X) is one of the most common mutations identified in Tcell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients, the specific role of PHF6R274X in hematopoiesis remains unexplored. Here, we engineered a knock-in mouse line with conditional expression of Phf6R274X-mutated protein in the hematopoietic system (Phf6R274X mouse). The Phf6R274X mice displayed an enlargement of hematopoietic stem cells (HSCs) compartment and increased proportion of Tcells in bone marrow. More Phf6R274X Tcells were in activated status than control. Moreover, Phf6R274X mutation led to enhanced self-renewal and biased Tcells differentiation of HSCs as assessed by competitive transplantation assays. RNA-sequencing analysis confirmed that Phf6R274X mutation altered the expression of key genes involved in HSC self-renewal and Tcell activation. Our study demonstrated that Phf6R274X plays a critical role in fine-tuning Tcells and HSC homeostasis.