Germline Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia

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Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia. Here we report two unrelated kindreds with inherited mutations in ETV6, the gene encoding the transcription factor ETS variant 6. These families were characterized by a low platelet count (thrombocytopenia) and acute lymphoblastic leukemia (ALL). Sequencing a panel of genes identified germline ETV6 mutations associated with leukemia and thrombocytopenia in multiple individuals tested. In one family, there was a substitution within the DNA binding domain of ETV6, termed L349P, and in the second there were five base pairs missing in ETV6 (N385fs), causing an abnormally truncated protein. We overexpressed the ETV6 mutants in the HeLa cell line and measured protein levels and localization within the cells. Instead of localizing to the nucleus, as expected for a transcription factor, the mutant proteins were found in the cytoplasm. The mutant proteins also showed decreased ability to regulate the expression of other genes typically suppressed by ETV6. These findings suggest that germline ETV6 mutations cause a new type of heritable leukemia. This discovery makes possible the pre-symptomatic diagnosis of leukemia susceptibility in families with germline ETV6 mutations, and also provides new information on the causes of leukemia.

Vyšlo v časopise: Germline Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005262
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005262

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