TY - JOUR
T1 - Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia
AU - Noetzli, Leila
AU - Lo, Richard W.
AU - Lee-Sherick, Alisa B.
AU - Callaghan, Michael
AU - Noris, Patrizia
AU - Savoia, Anna
AU - Rajpurkar, Madhvi
AU - Jones, Kenneth
AU - Gowan, Katherine
AU - Balduini, Carlo L.
AU - Pecci, Alessandro
AU - Gnan, Chiara
AU - De Rocco, Daniela
AU - Doubek, Michael
AU - Li, Ling
AU - Lu, Lily
AU - Leung, Richard
AU - Landolt-Marticorena, Carolina
AU - Hunger, Stephen
AU - Heller, Paula
AU - Gutierrez-Hartmann, Arthur
AU - Xiayuan, Liang
AU - Pluthero, Fred G.
AU - Rowley, Jesse W.
AU - Weyrich, Andrew S.
AU - Kahr, Walter H.A.
AU - Porter, Christopher C.
AU - Di Paola, Jorge
N1 - Funding Information:
We are grateful to the families studied for their contribution to this project. We are also grateful to T. Shaikh, R. Spritz and J. Murray for their insightful comments. This work was supported by the Postle Family Chair in Pediatric Cancer and Blood Disorders (J.D.P.) and by US National Institutes of Health grants HL112311 (A.S.W.) and GM103806 (J.W.R.). W.H.A.K. was supported by operating grants from the Canadian Institutes of Health Research (CIHR; MOP-81208 and MOP-259952). P.N. and A.S. were supported by grant GGP13082 from the Telethon Foundation.
Publisher Copyright:
© 2015 Nature America, Inc.
PY - 2015/5/30
Y1 - 2015/5/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84929130522&partnerID=8YFLogxK
U2 - 10.1038/ng.3253
DO - 10.1038/ng.3253
M3 - Article
C2 - 25807284
AN - SCOPUS:84929130522
VL - 47
SP - 535
EP - 538
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 5
ER -