PHF6 mutations in T-cell acute lymphoblastic leukemia

Pieter Van Vlierberghe; Teresa Palomero; Hossein Khiabanian; Joni Van Der Meulen; Mireia Castillo; Nadine Van Roy; Barbara De Moerloose; Jan Philippé; Sara González-García; María L. Toribio; Tom Taghon; Linda Zuurbier; Barbara Cauwelier; Christine J. Harrison; Claire Schwab; Markus Pisecker; Sabine Strehl; Anton W. Langerak; Jozef Gecz; Edwin Sonneveld; Rob Pieters; Elisabeth Paietta; Jacob M. Rowe; Peter H. Wiernik; Yves Benoit; Jean Soulier; Bruce Poppe; Xiaopan Yao; Carlos Cordon-Cardo; Jules Meijerink; Raul Rabadan; Frank Speleman; Adolfo Ferrando

doi:10.1038/ng.542

PHF6 mutations in T-cell acute lymphoblastic leukemia

Pieter Van Vlierberghe, Teresa Palomero, Hossein Khiabanian, Joni Van Der Meulen, Mireia Castillo, Nadine Van Roy, Barbara De Moerloose, Jan Philippé, Sara González-García, María L. Toribio, Tom Taghon, Linda Zuurbier, Barbara Cauwelier, Christine J. Harrison, Claire Schwab, Markus Pisecker, Sabine Strehl, Anton W. Langerak, Jozef Gecz, Edwin SonneveldRob Pieters, Elisabeth Paietta, Jacob M. Rowe, Peter H. Wiernik, Yves Benoit, Jean Soulier, Bruce Poppe, Xiaopan Yao, Carlos Cordon-Cardo, Jules Meijerink, Raul Rabadan, Frank Speleman, Adolfo Ferrando

Oncology

Research output: Contribution to journal › Article › peer-review

247 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	338-342
Number of pages	5
Journal	Nature Genetics
Volume	42
Issue number	4
DOIs	https://doi.org/10.1038/ng.542
State	Published - Apr 2010

ASJC Scopus subject areas

Genetics

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10.1038/ng.542

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Van Vlierberghe, P., Palomero, T., Khiabanian, H., Van Der Meulen, J., Castillo, M., Van Roy, N., De Moerloose, B., Philippé, J., González-García, S., Toribio, M. L., Taghon, T., Zuurbier, L., Cauwelier, B., Harrison, C. J., Schwab, C., Pisecker, M., Strehl, S., Langerak, A. W., Gecz, J., ... Ferrando, A. (2010). PHF6 mutations in T-cell acute lymphoblastic leukemia. Nature Genetics, 42(4), 338-342. https://doi.org/10.1038/ng.542

Van Vlierberghe, P, Palomero, T, Khiabanian, H, Van Der Meulen, J, Castillo, M, Van Roy, N, De Moerloose, B, Philippé, J, González-García, S, Toribio, ML, Taghon, T, Zuurbier, L, Cauwelier, B, Harrison, CJ, Schwab, C, Pisecker, M, Strehl, S, Langerak, AW, Gecz, J, Sonneveld, E, Pieters, R, Paietta, E, Rowe, JM, Wiernik, PH, Benoit, Y, Soulier, J, Poppe, B, Yao, X, Cordon-Cardo, C, Meijerink, J, Rabadan, R, Speleman, F & Ferrando, A 2010, 'PHF6 mutations in T-cell acute lymphoblastic leukemia', Nature Genetics, vol. 42, no. 4, pp. 338-342. https://doi.org/10.1038/ng.542

@article{8b79181fd88e4c179afce1ddadf7f2e2,

title = "PHF6 mutations in T-cell acute lymphoblastic leukemia",

abstract = "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.",

author = "{Van Vlierberghe}, Pieter and Teresa Palomero and Hossein Khiabanian and {Van Der Meulen}, Joni and Mireia Castillo and {Van Roy}, Nadine and {De Moerloose}, Barbara and Jan Philipp{\'e} and Sara Gonz{\'a}lez-Garc{\'i}a and Toribio, {Mar{\'i}a L.} and Tom Taghon and Linda Zuurbier and Barbara Cauwelier and Harrison, {Christine J.} and Claire Schwab and Markus Pisecker and Sabine Strehl and Langerak, {Anton W.} and Jozef Gecz and Edwin Sonneveld and Rob Pieters and Elisabeth Paietta and Rowe, {Jacob M.} and Wiernik, {Peter H.} and Yves Benoit and Jean Soulier and Bruce Poppe and Xiaopan Yao and Carlos Cordon-Cardo and Jules Meijerink and Raul Rabadan and Frank Speleman and Adolfo Ferrando",

note = "Funding Information: 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{\textquoteright}s Plan Nacional (BFU 2007-60990 and PlanE2009-0110 to M.L.T.), Comunidad de Madrid (S-SAL0304-2006 to M.L.T.), Fundaci{\'o}n MM (M.L.T.), Instituto de Salud Carlos III (RECAVA RD06/0014/1012 to M.L.T.), an Institutional Grant from the Fundaci{\'o}n Ram{\'o}n Areces (M.L.T.), the Alex{\textquoteright}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 Ram{\'o}n y Cajal and Ciudad Sanitaria La Paz (Madrid, Spain) for thymus samples.",

year = "2010",

month = apr,

doi = "10.1038/ng.542",

language = "English (US)",

volume = "42",

pages = "338--342",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - PHF6 mutations in T-cell acute lymphoblastic leukemia

AU - Van Vlierberghe, Pieter

AU - Palomero, Teresa

AU - Khiabanian, Hossein

AU - Van Der Meulen, Joni

AU - Castillo, Mireia

AU - Van Roy, Nadine

AU - De Moerloose, Barbara

AU - Philippé, Jan

AU - González-García, Sara

AU - Toribio, María L.

AU - Taghon, Tom

AU - Zuurbier, Linda

AU - Cauwelier, Barbara

AU - Harrison, Christine J.

AU - Schwab, Claire

AU - Pisecker, Markus

AU - Strehl, Sabine

AU - Langerak, Anton W.

AU - Gecz, Jozef

AU - Sonneveld, Edwin

AU - Pieters, Rob

AU - Paietta, Elisabeth

AU - Rowe, Jacob M.

AU - Wiernik, Peter H.

AU - Benoit, Yves

AU - Soulier, Jean

AU - Poppe, Bruce

AU - Yao, Xiaopan

AU - Cordon-Cardo, Carlos

AU - Meijerink, Jules

AU - Rabadan, Raul

AU - Speleman, Frank

AU - Ferrando, Adolfo

N1 - Funding Information: 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.

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

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JO - Nature Genetics

JF - Nature Genetics

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ER -

PHF6 mutations in T-cell acute lymphoblastic leukemia

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