PHF6 mutations in T-cell acute lymphoblastic leukemia

Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. 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.

[1]  M. Borjeson,et al.  An X-linked, recessively inherited syndrome characterized by grave mental deficiency, epilepsy, and endocrine disorder. , 2009, Acta medica Scandinavica.

[2]  H. Willard,et al.  Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  H. Willard,et al.  A first-generation X-inactivation profile of the human X chromosome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Shaw,et al.  Mutations in PHF6 are associated with Börjeson–Forssman–Lehmann syndrome , 2002, Nature Genetics.

[5]  E. Lander,et al.  Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. , 2002, Cancer cell.

[6]  R. Gelber,et al.  Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Gécz,et al.  The clinical picture of the Börjeson–Forssman–Lehmann syndrome in males and heterozygous females with PHF6 mutations , 2004, Clinical genetics.

[8]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[9]  F. Sigaux,et al.  HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). , 2005, Blood.

[10]  N. Lowndes,et al.  DNA Repair: The Importance of Phosphorylating Histone H2AX , 2005, Current Biology.

[11]  W. Kamps,et al.  The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols. , 2006, Haematologica.

[12]  Anne E Carpenter,et al.  A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen , 2006, Cell.

[13]  V. Kalscheuer,et al.  Impact of low copy repeats on the generation of balanced and unbalanced chromosomal aberrations in mental retardation , 2006, Cytogenetic and Genome Research.

[14]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

[15]  B. Nadel,et al.  The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. , 2007, Blood.

[16]  Rob Pieters,et al.  Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia , 2007, Nature Genetics.

[17]  J. Gécz,et al.  Protein and gene expression analysis of Phf6, the gene mutated in the Börjeson-Forssman-Lehmann Syndrome of intellectual disability and obesity. , 2007, Gene expression patterns : GEP.

[18]  Jeannie T. Lee,et al.  X chromosome dosage compensation: how mammals keep the balance. , 2008, Annual review of genetics.

[19]  S. Elledge,et al.  A quantitative atlas of mitotic phosphorylation , 2008, Proceedings of the National Academy of Sciences.

[20]  Andrew P. Stubbs,et al.  The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. , 2007, Blood.

[21]  E. Raetz,et al.  Molecular pathogenesis of T-cell leukaemia and lymphoma , 2008, Nature Reviews Immunology.

[22]  C. Allis,et al.  PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. , 2008, Mutation research.

[23]  A. Ferrando,et al.  T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). , 2009, Blood.

[24]  J. Maguire,et al.  Solution Hybrid Selection with Ultra-long Oligonucleotides for Massively Parallel Targeted Sequencing , 2009, Nature Biotechnology.

[25]  Michael Brudno,et al.  SHRiMP: Accurate Mapping of Short Color-space Reads , 2009, PLoS Comput. Biol..

[26]  A. Ferrando,et al.  CSL–MAML-dependent Notch1 signaling controls T lineage–specific IL-7Rα gene expression in early human thymopoiesis and leukemia , 2009, The Journal of experimental medicine.

[27]  A. Ferrando,et al.  ParMap, an algorithm for the identification of small genomic insertions and deletions in nextgen sequencing data , 2010, BMC Research Notes.

[28]  ParMap, an Algorithm for the Identification of Complex Genomic Variations in Nextgen Sequencing Data , 2010 .

[29]  Claire Schwab,et al.  Acute lymphoblastic leukaemia. , 2011, Methods in molecular biology.