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 (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.

SUBMITTER: Lan Y 

PROVIDER: S-EPMC10241978 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature