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

Satoru Miyagi; Patrycja Sroczynska; Yuko Kato; Yaeko Nakajima-Takagi; Motohiko Oshima; Ola Rizq; Naoya Takayama; Atsunori Saraya; Seiya Mizuno; Fumihiro Sugiyama; Satoru Takahashi; Yumi Matsuzaki; Jesper Christensen; Kristian Helin; Atsushi Iwama

doi:10.1182/blood.2019000468

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

Satoru Miyagi, Patrycja Sroczynska, Yuko Kato, Yaeko Nakajima-Takagi, Motohiko Oshima, Ola Rizq, Naoya Takayama, Atsunori Saraya, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Yumi Matsuzaki, Jesper Christensen, Kristian Helin^*, Atsushi Iwama

^*Corresponding author for this work

11 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Blood
Volume	133
Issue number	23
Pages (from-to)	2495-2506
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood.2019000468
Publication status	Published - 6 Jun 2019

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@article{f577b53de22d4faca5059d629efbd8d1,

title = "The chromatin binding protein Phf6 restricts the self-renewal of hematopoietic stem cells",

abstract = "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.",

author = "Satoru Miyagi and Patrycja Sroczynska and Yuko Kato and Yaeko Nakajima-Takagi and Motohiko Oshima and Ola Rizq and Naoya Takayama and Atsunori Saraya and Seiya Mizuno and Fumihiro Sugiyama and Satoru Takahashi and Yumi Matsuzaki and Jesper Christensen and Kristian Helin and Atsushi Iwama",

note = "Copyright {\textcopyright} 2019 American Society of Hematology.",

year = "2019",

month = jun,

day = "6",

doi = "10.1182/blood.2019000468",

language = "English",

volume = "133",

pages = "2495--2506",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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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

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 -

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

Abstract

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