84295

PHF6

BFLS|BORJ|CENP-31;PHD finger protein 6;PHF6;PHD finger protein 6

PHD-like zinc finger protein|centromere protein 31

Xq26.3

protein-coding

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.

INTRODUCTION: Somatic mutations in plant homeodomain finger protein 6 (PHF6) gene have recently been reported in T-cell acute lymphoblastic leukemia (T-ALL), strongly suggesting its role in the pathogenesis of human cancers. MATERIALS ANDMETHODS: To see whether the PHF6 mutation occurs in other malignancies, we analyzed entire coding sequences of PHF6 in 231 hematologic malignancies [105 acute myelogenous leukemias (AML), 66 pre-B-ALL, 23 T-ALL, one undifferentiated acute leukemia and 36 multiple myelomas] by single-strand conformation polymorphism assay. Also, we analyzed the mutation in 236 solid cancers, including 41 lung, 39 hepatocellular (HCC), 36 breast, 40 colorectal, 40 gastricand 40 prostate carcinomas. RESULTS: In the hematologic malignancies, there were11 PHF6 mutations that were detected not only in T-ALL (34.7%) (five adult and three childhood T-ALL), but also in two AML (1.9%) (one acute monocytic leukemiaand one AML minimally differentiated). In addition, there was a PHF6 mutation inthe HCC (2.6%). The PHF6 mutations were detected in both male and female patients, and consisted of six frameshift, three nonsense and two intron mutations. CONCLUSION: Our data suggest that PHF6 mutation might play a role in tumorigenesis not only of T-ALL, but also of AML and HCC.