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Ref Type Journal Article
PMID (25807284)
Authors Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, Rajpurkar M, Jones K, Gowan K, Balduini CL, Pecci A, Gnan C, De Rocco D, Doubek M, Li L, Lu L, Leung R, Landolt-Marticorena C, Hunger S, Heller P, Gutierrez-Hartmann A, Xiayuan L, Pluthero FG, Rowley JW, Weyrich AS, Kahr WH, Porter CC, Di Paola J
Title Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.
Journal Nature genetics
Vol 47
Issue 5
Date 2015 May
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ETV6 P214L missense loss of function ETV6 P214L lies within the linker domain of the Etv6 protein (PMID: 25581430). P214L results in decreased Etv6 transcriptional repression and delayed megakaryocyte maturation in cell culture (PMID: 25807284).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 inact mut acute lymphoblastic leukemia not applicable N/A Clinical Study Risk Factor In multiple clinical studies, ETV6 inactivating germline mutations were shown to be a risk factor for the development of acute lymphocytic leukemia (PMID: 26522332, PMID: 26102509, PMID: 25807284). 25807284 26102509 26522332