Some 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.

Children's Hospital of Michigan Wayne State University Detroit MI USA

Department of Biochemistry and Molecular Genetics University of Colorado AMC Aurora Colorado USA

Department of Biochemistry University of Toronto Toronto Ontario Canada

Department of Internal Medicine Haematology Oncology University Hospital Brno

Department of Internal Medicine IRCCS Policlinico San Matteo Foundation University of Pavia Pavia Italy

Department of Internal Medicine University of Utah Salt Lake City Utah USA

Department of Medical Sciences University of Trieste Trieste Italy

Department of Medicine University of Toronto Division of Rheumatology University Health Network Toronto Western Hospital Toronto Ontario Canada

Department of Paediatrics Division of Haematology Oncology University of Toronto and The Hospital for Sick Children Toronto Ontario Canada

Department of Pathology University of Colorado AMC Aurora Colorado USA

Department of Pediatrics University of Colorado Anschutz Medical Campus Aurora Colorado CO USA

Departments of Medicine University of Colorado AMC Aurora Colorado USA

Human Medical Genetics and Genomics Program University of Colorado AMC Aurora Colorado USA

Institute for Maternal and Child Health IRCCS Burlo Garofolo Trieste Italy

Instituto de Investigaciones Medicas Alfredo Lanari Universidad de Buenos Aires Buenos Aires Argentina

Molecular Medicine Program University of Utah Salt Lake City Utah USA

Program in Cell Biology Research Institute The Hospital for Sick Children Toronto Ontario Canada

Oncotarget. 2015 Jul 10;6(19):16830-1. doi: 10.18632/oncotarget.4842. PubMed

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Overt and covert genetic causes of pediatric acute lymphoblastic leukemia

Bone Marrow Stromal Cell Regeneration Profile in Treated B-Cell Precursor Acute Lymphoblastic Leukemia Patients: Association with MRD Status and Patient Outcome

Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia

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BioProject
PRJNA276621

SRA
SRP056053

dbGaP
PHS000873.V1.P1