PHF6 mutations in T-cell acute lymphoblastic leukemia

• Published in: Nature genetics Vol. 42; no. 4; pp. 338 - 342
• Main Authors: Van Vlierberghe, Pieter, Palomero, Teresa, Khiabanian, Hossein, Van der Meulen, Joni, Castillo, Mireia, Van Roy, Nadine, De Moerloose, Barbara, Philippé, Jan, González-García, Sara, Toribio, María L, Taghon, Tom, Zuurbier, Linda, Cauwelier, Barbara, Harrison, Christine J, Schwab, Claire, Pisecker, Markus, Strehl, Sabine, Langerak, Anton W, Gecz, Jozef, Sonneveld, Edwin, Pieters, Rob, Paietta, Elisabeth, Rowe, Jacob M, Wiernik, Peter H, Benoit, Yves, Soulier, Jean, Poppe, Bruce, Yao, Xiaopan, Cordon-Cardo, Carlos, Meijerink, Jules, Rabadan, Raul, Speleman, Frank, Ferrando, Adolfo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2010; Nature Publishing Group
• Subjects: 631/208/2489/68; 631/208/727/2000; 631/67/581; 692/699/67/1990/283/2125; Acute lymphocytic leukemia; Adult; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carrier Proteins - genetics; Cell cycle; Child; Chromosomes; Chromosomes, Human, X; Comparative Genomic Hybridization; DNA Copy Number Variations; DNA repair; Female; Females; Gene Function; Gene mutations; Genes; Genes, Tumor Suppressor; Genetic aspects; Genetic Linkage; Genetic testing; Genetics; Health aspects; Homeodomain Proteins - genetics; Human Genetics; Humans; Kinases; letter; Leukemia; Male; Males; Mutation; Physiological aspects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proteins; Proto-Oncogene Proteins - genetics; Repressor Proteins; Risk factors; Transcription factors; Tumor suppressor genes; Tumors; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.542

Adolfo Ferrando and colleagues identify frequent inactivating mutations and deletions in the X chromosome gene PHF6 in T-cell acute lymphoblastic leukemia. PHF6 mutations are found almost exclusively in males and are associated with leukemias driven by aberrant expression of TLX1 and TLX3 . Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer 1 , 2 . T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males 3 . 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.