Informace o publikaci

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

Autoři	NOETZLI Leila LO Richard W. LEE-SHERICK Alisa B. CALLAGHAN Michael NORIS Patrizia SAVOIA Anna RAJPURKAR Madhvi JONES Kenneth GOWAN Katherine BALDUINI Carlo L. PECCI Alessandro GNAN Chiara DE ROCCO Daniela DOUBEK Michael LI Ling LU Lily LEUNG Richard LANDOLT-MARTICORENA Carolina HUNGER Stephen HELLER Paula GUTIERREZ-HARTMANN Arthur LIANG Xiayuan PLUTHERO Fred G. ROWLEY Jesse W. WEYRICH Andrew S. KAHR Walter H.A. PORTER Christopher C. DI JORGE Paola
Rok publikování	2015
Druh	Článek v odborném periodiku
Časopis / Zdroj	Nature genetics
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
Doi	http://dx.doi.org/10.1038/ng.3253
Obor	Onkologie a hematologie
Klíčová slova	acute lymphoblastic leukemia; alternative RNA splicing; amino acid substitution;
Popis	Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia(1,2). 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.