The chromatin-binding protein Phf6 restricts the self-renewal of hematopoietic stem cells

Recurrent inactivating mutations have been identified in the X-linked plant homeodomain finger protein 6 (PHF6) gene, encoding a chromatin-binding transcriptional regulator protein, in various hematological malignancies. However, the role of PHF6 in normal hematopoiesis and its tumor-suppressor function remain largely unknown. We herein generated mice carrying a floxed Phf6 allele and inactivated Phf6 in hematopoietic cells at various developmental stages. The Phf6 deletion in embryos augmented the capacity of hematopoietic stem cells (HSCs) to proliferate in cultures and reconstitute hematopoiesis in recipient mice. The Phf6 deletion in neonates and adults revealed that cycling HSCs readily acquired an advantage in competitive repopulation upon the Phf6 deletion, whereas dormant HSCs only did so after serial transplantations. Phf6-deficient HSCs maintained an enhanced repopulating capacity during serial transplantations; however, they did not induce any hematological malignancies. Mechanistically, Phf6 directly and indirectly activated downstream effectors in tumor necrosis factor α (TNFα) signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFα signaling, thereby conferring resistance against the TNFα-mediated growth inhibition on HSCs. Collectively, these results not only define Phf6 as a novel negative regulator of HSC self-renewal, implicating inactivating PHF6 mutations in the pathogenesis of hematological mali...

Source: Blood - June 5, 2019 Category: Hematology Authors: Miyagi, S., Sroczynska, P., Kato, Y., Nakajima-Takagi, Y., Oshima, M., Rizq, O., Takayama, N., Saraya, A., Mizuno, S., Sugiyama, F., Takahashi, S., Matsuzaki, Y., Christensen, J., Helin, K., Iwama, A. Tags: Hematopoiesis and Stem Cells Source Type: research