PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation

Transcriptional control of hematopoiesis involves complex regulatory networks and functional perturbations in one of these components often results in malignancies. Loss-of-function mutations in , encoding a presumed epigenetic regulator, have been primarily described in T cell acute lymphoblastic leukemia (T-ALL) and the first insights into its function in normal hematopoiesis only recently emerged from mouse modeling experiments. Here, we investigated the role of PHF6 in human blood cell development by performing knockdown studies in cord blood and thymus-derived hematopoietic precursors to evaluate the impact on lineage differentiation in well-established models. Our findings reveal that levels differentially impact the differentiation of human hematopoietic progenitor cells into various blood cell lineages, with prominent effects on lymphoid and erythroid differentiation. We show that loss of PHF6 results in accelerated human T cell development through reduced expression of and its downstream target genes. This functional interaction in developing thymocytes was confirmed using a -deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced or notch1 activation. In summary, our work reveals that appropriate control of expression is important for normal human hematopoiesis and provides clues towards the role of in T-ALL development.