期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2020.599472
关键词
hematopoiesis; PHF6; NOTCH; zebrafish; T cell development
资金
- Odysseus program of the Fund for Scientific Research Flanders (FWO Vlaanderen)
- FWO (FWO Vlaanderen) [G.0202.09, G.0869.10N, 3G056413N, G037918N, 3GA00113N, 3G065614, G.0C47.13N, G0B2913N, G037514N, 3G002711]
- Concerted Research Action of Ghent University (GOA) [BOF18-GOA-024, 01G01910]
- Interuniversity Attraction Poles Program from the Belgian Science Policy [IUAP P7/03, P7/39]
- BOF
- Stichting tegen Kanker
- Villa Joep
- Kom op tegen Kanker
- IWT Vlaanderen
- Alex's Lemonade Stand Foundation
- Live Like Bella Foundation for Childhood Cancer
- American Cancer Society
- NIH [R01CA211734-01A1, 5F32DK098875]
- Massachusetts General Hospital (MGH) Howard Goodman Fellowship
- MGH Pathology CNY Flow Cytometry Core shared instrumentation grant [1S10RR023440-01A]
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.
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