Abstract
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 PHF6, 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 in vitro models. Our findings reveal that PHF6 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 NOTCH1 and its downstream target genes. This functional interaction in developing thymocytes was confirmed in vivo using a phf6-deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced phf6 or notch1 activation. In summary, our work reveals that appropriate control of PHF6 expression is important for normal human hematopoiesis and provides clues towards the role of PHF6 in T-ALL development.
Highlights
Hematopoietic lineage development is hierarchically organized and involves highly dynamic processes in which hematopoietic stem cells balance between self-renewal and differentiation to generate a wide variety of blood cell types
Consistent with the strong association between loss-of-function PHF6 mutations and activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) (Wang et al, 2011; Li et al, 2016), we reveal that NOTCH1 expression and signaling is dependent on PHF6 expression during normal T cell development
We observed similar developmental effects for both PHF6 and Notch activity in our in vitro PHF6 loss-of-function experiments for human T cell development. We independently confirmed these findings in vivo using a pfh6 knock-out zebrafish model. The findings from this manuscript are consistent with our previous work on the role of Notch signaling during human T cell development
Summary
Hematopoietic lineage development is hierarchically organized and involves highly dynamic processes in which hematopoietic stem cells balance between self-renewal and differentiation to generate a wide variety of blood cell types This process is tightly controlled by various key transcriptional regulators that integrate environmental cues, such as growth factors and cellintrinsic signals, including epigenetic modifications, to dictate the developmental outcome (Dege and Hagman, 2014; De Obaldia and Bhandoola, 2015; Rothenberg et al, 2016). Many of these developmental genes have been identified through the study of loss- or gain-of-function genetic alterations in hematopoietic malignancies. Multiple factors that work in crosstalk with the NOTCH1 pathway to tightly control normal T cell development have been described and are still a major subject of study, as exemplified by our recent work on the role of GATA3 in the process of T-lineage commitment (Van de Walle et al, 2016)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
