PHF6 mutations in T-cell acute lymphoblastic leukemia

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.
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.).