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PHF6 mutations in T-cell acute lymphoblastic leukemia

Nature Genetics volume 42, pages 338–342 (2010)Cite this article

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Abstract

Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer1,2. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males3. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

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Figure 1: Next-generation sequencing and microarray-based comparative genomic hybridization (array-CGH) analysis of the X chromosome identifies PHF6 mutations in human T-cell acute lymphoblastic leukemia (T-ALL).
Figure 2: PHF6 mutations and expression in T-cell acute lymphoblastic leukemia (T-ALL) lymphoblasts.
Figure 3: PHF6 expression in T-cell acute lymphoblastic leukemia (T-ALL) lymphoblasts.
Figure 4: Clinical and biological characteristics associated with PHF6 mutations in T-cell acute lymphoblastic leukemia (T-ALL).

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Acknowledgements

This study was supported by the Fund for Scientific Research (FWO) Flanders (postdoctoral grants to P.V.V. and T.T., PhD grant to J.V.d.M., senior clinical investigator award to B.P. and project grants G.0198.08 and G.0869.10N to F.S.); the GOA-UGent (grant no. 12051203); the IWT-Vlaanderen (SBO grant no. 060848); the Children Cancer Fund Ghent (F.S.); Leukemia Research UK (C.J.H.); the Stichting Kinderen Kankervrij (KiKa; grant no. KiKa 2007-012 to L.Z.); the Belgian Program of Interuniversity Poles of Attraction; the Belgian Foundation against Cancer; the Austrian Ministry of Science and Research (GEN-AU Child, GZ 200.136/1-VI/1/2005 to S.S.), the US National Library of Medicine (1R01LM010140-01 to R.R. and H.K.); the ECOG and DCOG tumor banks; grants from Spain's Plan Nacional (BFU 2007-60990 and PlanE2009-0110 to M.L.T.), Comunidad de Madrid (S-SAL0304-2006 to M.L.T.), Fundación MM (M.L.T.), Instituto de Salud Carlos III (RECAVA RD06/0014/1012 to M.L.T.), an Institutional Grant from the Fundación Ramón Areces (M.L.T.), the Alex's Lemonade Stand Foundation Young Investigator Award (T.P.); a US Northeast Biodefense Center ARRA award (U54-AI057158 to R.R.); the US National Institutes of Health (R01CA120196 and R01CA129382 to A.F.); the Rally across America Foundation (A.F); the Swim across America Foundation (A.F.); the Golfers against Cancer Foundation (A.F.); and a Leukemia and Lymphoma Society Scholar Award (A.F.). We thank the Pediatric Cardiosurgery Units from Centro Especial Ramón y Cajal and Ciudad Sanitaria La Paz (Madrid, Spain) for thymus samples.

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Author notes

  1. Pieter Van Vlierberghe and Teresa Palomero: These authors contributed equally to this work.

  2. Frank Speleman and Adolfo Ferrando: These authors jointly directed this work.

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA

    Pieter Van Vlierberghe, Teresa Palomero & Adolfo Ferrando

  2. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Pieter Van Vlierberghe, Joni Van der Meulen, Nadine Van Roy, Bruce Poppe & Frank Speleman

  3. Department of Pediatric Oncology/Hematology, Erasmus MC, Rotterdam, The Netherlands

    Pieter Van Vlierberghe, Linda Zuurbier, Rob Pieters & Jules Meijerink

  4. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    Teresa Palomero, Mireia Castillo, Carlos Cordon-Cardo & Adolfo Ferrando

  5. Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA

    Hossein Khiabanian & Raul Rabadan

  6. Department of Pediatric Hemato-Oncology, Ghent University Hospital, Ghent, Belgium

    Barbara De Moerloose & Yves Benoit

  7. Department of Clinical Chemistry, Immunology and Microbiology, Ghent University Hospital, Ghent, Belgium

    Jan Philippé & Tom Taghon

  8. Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain

    Sara González-García & María L Toribio

  9. Department of Hematology, Hospital St-Jan, Bruges, Belgium

    Barbara Cauwelier

  10. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

    Christine J Harrison & Claire Schwab

  11. Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria

    Markus Pisecker & Sabine Strehl

  12. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    Anton W Langerak

  13. Department of Genetics and Molecular Pathology, University of Adelaide, Adelaide, Australia

    Jozef Gecz

  14. Department of Pediatrics, University of Adelaide, Adelaide, Australia

    Jozef Gecz

  15. On behalf of the Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    Edwin Sonneveld & Rob Pieters

  16. Montefiore Medical Center North, Bronx, New York, USA

    Elisabeth Paietta & Peter H Wiernik

  17. Rambam Medical Center and Technion, Israel Institute of Technology, Haifa, Israel

    Jacob M Rowe

  18. Hematology Laboratory APHP, INSERM U944, Hôpital Saint Louis, Paris, France

    Jean Soulier

  19. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Xiaopan Yao

  20. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA

    Adolfo Ferrando

Authors
  1. Pieter Van Vlierberghe
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Contributions

P.V.V. performed array-CGH and mutation analysis of PHF6 and wrote the manuscript. T.P. performed exon capture and next-generation sequencing of T-ALL samples and wrote the manuscript. H.K. analyzed next-generation sequencing data. J.V.d.M. performed additional array-CGH analysis and PHF6 mutation screening in T-ALL and BCP-ALL samples. T.T., N.V.R. and A.W.L. performed experiments. M.C. and C.C.-C. performed and analyzed histological and immunohistochemical staining. J.P. collaborated on PHF6 mutation screening in BCP-ALL samples. C.J.H. and C.S. collaborated on additional screening for genomic PHF6 deletions in T-ALL. Y.B., B.D.M. and B.C. collaborated on the PHF6 mutation screening. R.P., M.P., S.S. and J.S. collaborated on the multicenter array-CGH study. S.G.-G. and M.L.T. performed the isolation of T-cell progenitor cells for expression analysis of PHF6. X.Y. performed survival analysis of ECOG T-ALL patients. J.G. provided critical reagents and discussion. E.S. provided samples and correlative clinical data from DCOG. E.P., J.M.R. and P.H.W. provided samples and correlative clinical data from ECOG. J.M. and L.Z. collaborated on the multicenter array-CGH study and PHF6 mutation analysis, provided molecular data on the characterization of T-ALL and performed survival analysis of PHF6 mutations in the DCOG series. R.R. designed and directed the analysis of next-generation sequencing results. F.S. and B.P. designed the studies and directed research. A.F. designed the studies, directed research and wrote the manuscript.

Corresponding author

Correspondence to Adolfo Ferrando.

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The authors declare no competing financial interests.

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Van Vlierberghe, P., Palomero, T., Khiabanian, H. et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet 42, 338–342 (2010). https://doi.org/10.1038/ng.542

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