TY - JOUR
T1 - The chromatin binding protein Phf6 restricts the self-renewal of hematopoietic stem cells
AU - Miyagi, Satoru
AU - Sroczynska, Patrycja
AU - Kato, Yuko
AU - Nakajima-Takagi, Yaeko
AU - Oshima, Motohiko
AU - Rizq, Ola
AU - Takayama, Naoya
AU - Saraya, Atsunori
AU - Mizuno, Seiya
AU - Sugiyama, Fumihiro
AU - Takahashi, Satoru
AU - Matsuzaki, Yumi
AU - Christensen, Jesper
AU - Helin, Kristian
AU - Iwama, Atsushi
N1 - Copyright © 2019 American Society of Hematology.
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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 a (TNFa) signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFa signaling, thereby conferring resistance against the TNFa-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 malignancies, but also indicate that a Phf6 deficiency alone is not sufficient to induce hematopoietic transformation.
AB - 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 a (TNFa) signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFa signaling, thereby conferring resistance against the TNFa-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 malignancies, but also indicate that a Phf6 deficiency alone is not sufficient to induce hematopoietic transformation.
U2 - 10.1182/blood.2019000468
DO - 10.1182/blood.2019000468
M3 - Journal article
C2 - 30917958
SN - 0006-4971
VL - 133
SP - 2495
EP - 2506
JO - Blood
JF - Blood
IS - 23
ER -