• Leila Noetzli, Richard W Lo, Alisa B Lee-Sherick, Michael Callaghan, Patrizia Noris, Anna Savoia, Madhvi Rajpurkar, Kenneth 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 Hunger, Paula Heller, Arthur Gutierrez-Hartmann, Liang Xiayuan, Fred G Pluthero, Jesse W Rowley, Andrew S Weyrich, Walter H A Kahr, Christopher C Porter, and Jorge Di Paola.
• 1] Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, USA. [2] Human Medical Genetics and Genomics Program, University of Colorado AMC, Aurora, Colorado, USA.
• Nat. Genet. 2015 May 1; 47 (5): 535-8.

AbstractSome familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. 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.

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