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Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia

2015; Nature Portfolio; Volume: 47; Issue: 5 Linguagem: Inglês

10.1038/ng.3253

1546-1718

Leila Noetzli, Richard Lo, Alisa B. Lee‐Sherick, Michael U. Callaghan, Patrizia Noris, Anna Savoia, Madhvi Rajpurkar, Kenneth L. Jones, Katherine Gowan, Carlo L. Balduini, Alessandro Pecci, Chiara Gnan, Daniela De Rocco, Michael Doubek, Ling Li, Lily Lu, Richard Leung, Carolina Landolt-Marticorena, Stephen P. Hunger, Paula G. Heller, Arthur Gutierrez‐Hartmann, Xiayuan Liang, Fred G. Pluthero, Jesse W. Rowley, Andrew S. Weyrich, Walter H.A. Kahr, Christopher C. Porter, Jorge Di Paola,

Chronic Lymphocytic Leukemia Research

Jorge Di Paola, Christopher Porter, Walter Kahr and colleagues report germline mutations in the transcriptional repressor gene ETV6 in three families with thrombocytopenia and elevated red blood cell volume. All three mutations affect the ability of ETV6 to repress transcription of a reporter construct, and the two protein-altering mutations affect megakaryocyte development. Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia1,2. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.