@article{470ec56f177e4eec87de780e42e2d91b,
title = "Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia",
abstract = "Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.",
keywords = "ALL, IKAROS, IKZF1, acute lymphoblastic leukemia, drug response, familial leukemia, germline genetic variation, immunodeficiency, predisposition",
author = "Churchman, {Michelle L.} and Maoxiang Qian and {te Kronnie}, Geertruy and Ranran Zhang and Wenjian Yang and Hui Zhang and Tobia Lana and Paige Tedrick and Rebekah Baskin and Katherine Verbist and Peters, {Jennifer L.} and Meenakshi Devidas and Eric Larsen and Moore, {Ian M.} and Zhaohui Gu and Chunxu Qu and Hiroki Yoshihara and Porter, {Shaina N.} and Pruett-Miller, {Shondra M.} and Gang Wu and Elizabeth Raetz and Martin, {Paul L.} and Bowman, {W. Paul} and Naomi Winick and Elaine Mardis and Robert Fulton and Martin Stanulla and Evans, {William E.} and Relling, {Mary V.} and Pui, {Ching Hon} and Hunger, {Stephen P.} and Loh, {Mignon L.} and Rupert Handgretinger and Nichols, {Kim E.} and Yang, {Jun J.} and Mullighan, {Charles G.}",
note = "Funding Information: We thank the Genome Sequencing Facility, Hartwell Center for Bioinformatics and Biotechnology, and the flow cytometry and cell sorting core facility of St. Jude Children's Research Hospital. This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; European Commission FP7, ERA-NET on Translational Cancer Research, TRANSCALL, Health-F2-2010-260791 (to M.S. and G.K.); Parents Association for Children with Cancer, Tuebingen (to R.H.); a St. Baldrick's Foundation Scholar award and Robert J. Arceci award (to C.G.M.); NIH grant P50 GM115279 to (to C.G.M., J.J.Y., M.V.R., and W.E.E.); National Cancer Institute grants P30 CA021765 (St. Jude Cancer Center support grant), U01CA176063 (to. J.J.Y.), R35 CA197695-01A1 (to C.G.M.); and grants to the Children's Oncology Group : CA98543 , CA114766 , CA98413 , CA180886 , and CA180899 . Funding Information: We thank the Genome Sequencing Facility, Hartwell Center for Bioinformatics and Biotechnology, and the flow cytometry and cell sorting core facility of St. Jude Children's Research Hospital. This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; European Commission FP7, ERA-NET on Translational Cancer Research, TRANSCALL, Health-F2-2010-260791 (to M.S. and G.K.); Parents Association for Children with Cancer, Tuebingen (to R.H.); a St. Baldrick's Foundation Scholar award and Robert J. Arceci award (to C.G.M.); NIH grant P50 GM115279 to (to C.G.M., J.J.Y., M.V.R., and W.E.E.); National Cancer Institute grants P30 CA021765 (St. Jude Cancer Center support grant), U01CA176063 (to. J.J.Y.), R35 CA197695-01A1 (to C.G.M.); and grants to the Children's Oncology Group: CA98543, CA114766, CA98413, CA180886, and CA180899. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "14",
doi = "10.1016/j.ccell.2018.03.021",
language = "English (US)",
volume = "33",
pages = "937--948.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}