Phf6 plays a role in hematopoiesis and thymopoiesis in zebrafish

T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of thymocytes and affects both children and adults. In T-ALL, multiple genetic lesions in oncogenes and tumor suppressor genes cooperatively contribute to leukemogenesis. Recently, our research group identified inactivating mutations and deletions in the PHF6 gene in 16% of pediatric and 38% of adult T-ALL patients. Although these frequencies suggest an important role for PHF6 as a tumor suppressor in T-ALL, the role of PHF6 in normal and malignant T-cell development remains largely unknown. Whole mount in situ hybridization (WISH) revealed phf6 expression in developing zebrafish in hematopoietic regions and in the thymus. Upon morpholino-mediated knockdown of phf6, WISH experiments demonstrated a normal onset of primitive hematopoiesis at 15 somites, while increased expression of lmo2, a marker for primitive hematopoiesis and erythropoiesis at 24hpf (hours post fertilization) can be observed. Moreover, also c-myb expression, a marker for definitive hematopoiesis, is increased in the caudal hematopoietic tissue at 36hpf after phf6 knockdown. Rag1 and rag2 are useful markers for following the development of lymphoid tissues since they are expressed together exclusively in immature lymphocytes. Interestingly, a significant reduction in thymus development and size could be observed in phf6 morphants at 5dpf (days post fertilization) using the transgenic zebrafish line tg(Rag2:GFP). In line with these results, strongly reduced rag1 expression was evident upon performing WISH on 5dpf phf6 knockdown embryos, as compared to control embryos. All together, our data provide strong evidence for an important role of phf6 in primitive hematopoiesis and thymopoiesis. Further studies will include phf6 knockout zebrafish to assess long-term effects and susceptibility to T-ALL formation in vivo.

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