PHF6: a conductor of HSC self-renewal

title201908

PHF6: a conductor of HSC self-renewal

C57BL/6-Phf6<em1Utr> (RBRC10186)

Fig_201908A
Fig_201908B

Courtesy of Satoru Miyagi, Ph.D.

(A) Strategy for competitive repopulating assays using the Mx1-Cre system. Mx1-Cre and Mx1-Cre;Phf6fl/y mice were injected with pIpC at 7 weeks of age and BM cells were harvested for competitive transplantation at 12 weeks of age. Ly5.2 BM cells were transplanted into lethally irradiated Ly5.1 recipient mice along with the same number of Ly5.1 WT BM cells. (B) The chimerism of donor cells in peripheral blood after transplantation.

 

Phf6 (plant homeodomain-like finger gene 6) is located on the X-chromosome and encodes a chromatin-binding protein with two zinc finger domains. Therefore, PHF6 is implicated to regulate gene transcription [1]. PHF6 is known to disease gene for one of the X-linked intellectual disability disorder; Börjeson-Forssman-Lehmann syndrome (OMIM#301900) [2]. In addition, it is reported that some patients of hematopoietic stem cell disorders (T-cell acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, etc.) have PHF6 inactivating mutations [3-5].
In conditional Phf6 knockout mice (RBRC10186) generated by CRISPR/Cas9 system, exons 4-5 of the Phf6 gene (encoding a zinc-finger domain) are flanked by loxP sites [6]. Using this strain, depositor (Dr. Miyagi) and his colleague depleted Phf6 gene in hematopoietic cells at various developmental stages and analyzed PHF6 function for hematopoiesis. As a result, they revealed that PHF6 restricts the self-renewal of HSCs (hematopoietic stem cells) and only Phf6 gene depletion is insufficient for induction of hematopoietic transformation. Therefore, conditional Phf6 knockout mice will offer the opportunity to understand the pathogenic and pathological mechanisms of PHF6-related diseases.

 

Depositor : Satoru Miyagi, Ph.D.
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University
(at the time of the strain deposition)
Strain name : C57BL/6-Phf6<em1Utr>
RBRC No. : RBRC10186
References : [1] Todd MA, Ivanochko D, Picketts DJ.
PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein.
Genes (Basel).; 6(2):325-52, 2015.
[2] Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, Lampe AK, Clayton-Smith J, Stewart H, van Ravenswaay CM, de Vries BB, Cox B, Grompe M, Ross S, Thomas P, Mulley JC, Gécz J.
Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome.
Nat Genet.; 32(4):661-5, 2002.
[3] Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A.
PHF6 mutations in T-cell acute lymphoblastic leukemia.
Nat Genet.; 42(4):338-42, 2010.
[4] Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, Nicolas C, Payer AR, Fernandez HF, Tallman MS, Paietta E, Melnick A, Vandenberghe P, Speleman F, Aifantis I, Cools J, Levine R, Ferrando A.
PHF6 mutations in adult acute myeloid leukemia.
Leukemia.; 25(1):130-4, 2011.
[5] Mori T, Nagata Y, Makishima H, Sanada M, Shiozawa Y, Kon A, Yoshizato T, Sato-Otsubo A, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ishiyama K, Miyawaki S, Mori H, Nakamaki T, Kihara R, Kiyoi H, Koeffler HP, Shih LY, Miyano S, Naoe T, Haferlach C, Kern W, Haferlach T, Ogawa S, Yoshida K.
Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms.
Leukemia.; 30(11):2270-2273, 2016.
[6] 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.
The chromatin-binding protein Phf6 restricts the self-renewal of hematopoietic stem cells.
Blood.; 133(23):2495-2506, 2019.

 

August 2019
Contact: Saori Mizuno, Ph.D.
Experimental Animal Division, RIKEN BioResource Research Center
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