T-Cell Acute Lymphoblastic Leukemia in Association With Borjeson-Forssman-Lehmann Syndrome Due To a Mutation in PHF6

Pediatric Blood & Cancer (Impact Factor: 2.56). 10/2010; 55(4):722 - 724. DOI: 10.1002/pbc.22574

ABSTRACT Börjeson–Forssman–Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL. Pediatr Blood Cancer. 2010;55:722–724. © 2010 Wiley-Liss, Inc.

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Available from: Katherine R Neas, Jun 21, 2015
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    ABSTRACT: The plant homeodomain finger 6 (PHF6) was originally identified as the gene mutated in the X-linked mental retardation disorder, Borjeson-Forssman-Lehmann syndrome (BFLS). Mutations in the PHF6 gene have also been associated to T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Approximately half of the disease-associated mutations are distributed in the second conserved extended PHD (ePHD2) domain of PHF6, indicating the functional importance of the ePHD2 domain. Here, we report the high resolution crystal structure of the ePHD2 domain of PHF6, which contains an N-terminal pre-PHD (C2HC zinc finger), a long linker, and an atypical PHD finger. PHF6-ePHD2 appears to fold as a novel integrated structural module. Structural analysis of PHF6-ePHD2 reveals pathological implication of PHF6 gene mutations in BFLS, T-ALL and AML. The binding experiments show that PHF6-ePHD2 can bind dsDNA, but not histones. We also demonstrate PHF6 protein directly interacts with the NuRD complex component RBBP4. Via this interaction, PHF6 exerts its transcriptional repression activity. Taken together, these data support the hypothesis that PHF6 may function as a transcriptional repressor using its ePHD domains binding to the promoter region of its repressed gene and this process was regulated by the NuRD complex which was recruited to the genomic target site by NoLS region of PHF6.
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