title: Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia.
abstract: Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York, United States of America.
authors.forename: Sabine
authors.initials: S
authors.lastname: Topka
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walsh
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Maria
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Danylo
authors.initials: D
authors.lastname: Villano
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Pragna
authors.initials: P
authors.lastname: Gaddam
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Rose B
authors.initials: RB
authors.lastname: McGee
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Quinn
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartford
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pappo
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, United States of America.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Pediatric Hematology/Oncology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Steinherz
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kasmintan
authors.initials: K
authors.lastname: Schrader
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Lincoln
authors.affiliation: Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Bussel
authors.affiliation: Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Lipkin
authors.affiliation: Structural Biology Program, Sloan Kettering Institute, New York, New York, United States of America.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Goldgur
authors.affiliation: Pediatric Hematology/Oncology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Mira
authors.initials: M
authors.lastname: Harit
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Mullighan
authors.affiliation: Pediatric Hematology/Oncology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Weintraub
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, United States of America; Seattle Children's Hospital, Seattle, Washington, United States of America.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York, United States of America; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013921:Thrombocytopenia / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein