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Oncogenes, Fusion Genes and Tumor Suppressor Genes

PHF6 mutations in adult acute myeloid leukemia

Abstract

Loss of function mutations and deletions encompassing the plant homeodomain finger 6 (PHF6) gene are present in about 20% of T-cell acute lymphoblastic leukemias (ALLs). Here, we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AMLs). Genetic lesions in PHF6 found in AMLs are frameshift and nonsense mutations distributed through the gene or point mutations involving the second plant homeodomain (PHD)-like domain of the protein. As in the case of T-ALL, where PHF6 alterations are found almost exclusively in males, mutations in PHF6 were seven times more prevalent in males than in females with AML. Overall, these results identify PHF6 as a tumor suppressor gene mutated in AML and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors.

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Acknowledgements

This study was supported by the Fund for Scientific Research (FWO) Flanders (postdoctoral grants to PVV and project grants G.0198.08 and G.0869.10N to FS); the GOA-UGent (Grant no. 12051203); the IWT-Vlaanderen (SBO Grant no. 060848); the Children Cancer Fund Ghent (FS); the Belgian Program of Interuniversity Poles of Attraction; the Belgian Foundation Against Cancer; the ECOG and MSKCC tumor banks; a Physical Sciences-Oncology Center grant from the NCI (RLL); the National Institutes of Health (R01CA120196 and R01CA129382 to AF); the Rally Across America Foundation (AF); the Swim Across America Foundation (AF) and the Golfers Against Cancer Foundation (AF). RLL is the Geoffrey Beene Junior Chair and an Early Career Award Recipient of the Howard Hughes Medical Institute. AF is a Leukemia and Lymphoma Society Scholar. We appreciate the assistance of Adriana Heguy with DNA resequencing.

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Correspondence to A Ferrando.

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PVV performed mutation analysis of PHF6 and wrote the manuscript. JP, OA and RL performed mutation analysis of PHF6 on the ECOG patient series (E1900). CL and IA performed the isolation of murine hematopoietic stem cell (HSC) and myeloid progenitor populations. EP and AM provided samples and correlative data from ECOG. MB, CN and AP provided samples and correlative data from Hospital Central de Asturias. PV, JC and FS provided samples and correlative data from the University Hospital Leuven. RL and CH provided samples and correlative data from MSKCC. AF designed the studies, directed research and wrote the manuscript.

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Van Vlierberghe, P., Patel, J., Abdel-Wahab, O. et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia 25, 130–134 (2011). https://doi.org/10.1038/leu.2010.247

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