{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:05:10Z","timestamp":1792677910586,"version":"4.5.0"},"reference-count":54,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA214608"],"award-info":[{"award-number":["R01CA214608"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001021","name":"Damon Runyon Cancer Research Foundation","doi-asserted-by":"publisher","award":["DRR-50-18"],"award-info":[{"award-number":["DRR-50-18"]}],"id":[{"id":"10.13039\/100001021","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Linde Family Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.<\/jats:p>","DOI":"10.7554\/elife.38430","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T08:00:47Z","timestamp":1533110447000},"source":"Crossref","is-referenced-by-count":496,"title":["Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome"],"prefix":"10.7554","volume":"7","author":[{"given":"Katherine A","family":"Donovan","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"An","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rados\u0142aw P","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingting C","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-8558","authenticated-orcid":true,"given":"Emma C","family":"Fink","sequence":"additional","affiliation":[{"name":"Division of Hematology, Brigham and Women\u2019s Hospital, Boston, United States"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany C","family":"Berry","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin L","family":"Ebert","sequence":"additional","affiliation":[{"name":"Division of Hematology, Brigham and Women\u2019s Hospital, Boston, United States"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7337-6306","authenticated-orcid":true,"given":"Eric S","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1111\/cga.12151","article-title":"Expanding the mutation and clinical spectrum of roberts syndrome","volume":"56","author":"Afifi","year":"2016","journal-title":"Congenital Anomalies"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"15398","DOI":"10.1038\/ncomms15398","article-title":"pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase","volume":"8","author":"An","year":"2017","journal-title":"Nature Communications"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"626","DOI":"10.3892\/etm.2012.847","article-title":"Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry","volume":"5","author":"Bai","year":"2013","journal-title":"Experimental and Therapeutic Medicine"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1159\/000459764","article-title":"The effect of thalidomide on a prosimian: the greater galago (Galago crassicaudatus)","volume":"6","author":"Butler","year":"1977","journal-title":"Journal of Medical Primatology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/nature17416","article-title":"Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome","volume":"531","author":"Cavadini","year":"2016","journal-title":"Nature"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/nsmb.2874","article-title":"Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs","volume":"21","author":"Chamberlain","year":"2014","journal-title":"Nature Structural & Molecular Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/s40262-016-0432-1","article-title":"Clinical pharmacokinetics and pharmacodynamics of lenalidomide","volume":"56","author":"Chen","year":"2017","journal-title":"Clinical Pharmacokinetics"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"4082","DOI":"10.1073\/pnas.91.9.4082","article-title":"Thalidomide is an inhibitor of angiogenesis","volume":"91","author":"D'Amato","year":"1994","journal-title":"PNAS"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1177\/0091270009335001","article-title":"Phase I study of oral lenalidomide in patients with refractory metastatic cancer","volume":"49","author":"Dahut","year":"2009","journal-title":"The Journal of Clinical Pharmacology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/nm.4128","article-title":"Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity","volume":"22","author":"Eichner","year":"2016","journal-title":"Nature Medicine"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"blood-2018-05-852798","DOI":"10.1182\/blood-2018-05-852798","article-title":"CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice","author":"Fink","year":"2018","journal-title":"Blood"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nature13527","article-title":"Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide","volume":"512","author":"Fischer","year":"2014","journal-title":"Nature"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1016\/j.cell.2011.10.035","article-title":"The molecular basis of CRL4DDB2\/CSA ubiquitin ligase architecture, targeting, and activation","volume":"147","author":"Fischer","year":"2011","journal-title":"Cell"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1111\/bjh.12708","article-title":"Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors ikaros and aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.)","volume":"164","author":"Gandhi","year":"2014","journal-title":"British Journal of Haematology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/bjh.12622","article-title":"Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity","volume":"164","author":"Gandhi","year":"2014","journal-title":"British Journal of Haematology"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1016\/j.celrep.2016.11.005","article-title":"RNF166 determines recruitment of adaptor proteins during antibacterial autophagy","volume":"17","author":"Heath","year":"2016","journal-title":"Cell Reports"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/BF00570141","article-title":"Embryotoxic effects of thalidomide derivatives on the non-human primate callithrix jacchus; 3. Teratogenic potency of the EM 12 enantiomers","volume":"62","author":"Heger","year":"1988","journal-title":"Archives of Toxicology"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s00280-012-2040-6","article-title":"Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration","volume":"71","author":"Hoffmann","year":"2013","journal-title":"Cancer Chemotherapy and Pharmacology"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1056\/NEJM196408272710904","article-title":"Thalidomide embryopathy in hybrid rabbits","volume":"271","author":"Ingalls","year":"1964","journal-title":"New England Journal of Medicine"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/nature19356","article-title":"High-throughput discovery of novel developmental phenotypes","volume":"537","author":"International Mouse Phenotyping Consortium","year":"2016","journal-title":"Nature"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a primary target of thalidomide teratogenicity","volume":"327","author":"Ito","year":"2010","journal-title":"Science"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.4161\/cc.7.9.5793","article-title":"Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects","volume":"7","author":"Knobloch","year":"2008","journal-title":"Cell Cycle"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1136\/jmg.40.7.473","article-title":"Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy","volume":"40","author":"Kohlhase","year":"2003","journal-title":"Journal of Medical Genetics"},{"key":"bib24","volume-title":"GeneReviews","author":"Kohlhase","year":"1993"},{"key":"bib25","volume-title":"GeneReviews","author":"Kohlhase","year":"2004"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/ng1707","article-title":"Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart","volume":"38","author":"Koshiba-Takeuchi","year":"2006","journal-title":"Nature Genetics"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nature14610","article-title":"Lenalidomide induces ubiquitination and degradation of CK1\u03b1 in del(5q) MDS","volume":"523","author":"Kr\u00f6nke","year":"2015","journal-title":"Nature"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1126\/science.1244851","article-title":"Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells","volume":"343","author":"Kr\u00f6nke","year":"2014","journal-title":"Science"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.2337\/db12-1030","article-title":"Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice","volume":"62","author":"Lee","year":"2013","journal-title":"Diabetes"},{"key":"bib30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(62)92665-X","article-title":"Thalidomide and congenital abnormalities","author":"Lenz","year":"1962","journal-title":"The Journal of American Medical Association"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1002\/tera.1420380303","article-title":"A short history of thalidomide embryopathy","volume":"38","author":"Lenz","year":"1988","journal-title":"Teratology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1126\/science.1244917","article-title":"The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins","volume":"343","author":"Lu","year":"2014","journal-title":"Science"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nature18611","article-title":"A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase","volume":"535","author":"Matyskiela","year":"2016","journal-title":"Nature"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"7150","DOI":"10.1021\/ac502040v","article-title":"MultiNotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes","volume":"86","author":"McAlister","year":"2014","journal-title":"Analytical Chemistry"},{"key":"bib35","first-page":"1358","article-title":"Thalidomide and congenital abnormalities","volume":"278","author":"McBride","year":"1961","journal-title":"The Journal of American Medical Association"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/nbt.3128","article-title":"C2H2 zinc finger proteins greatly expand the human regulatory lexicon","volume":"33","author":"Najafabadi","year":"2015","journal-title":"Nature Biotechnology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1007\/BF00316632","article-title":"Embryotoxic effects of thalidomide derivatives in the non-human primate callithrix jacchus. II. Elucidation of the susceptible period and of the variability of embryonic stages","volume":"61","author":"Neubert","year":"1988","journal-title":"Archives of Toxicology"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.molcel.2016.02.032","article-title":"Glutamine triggers Acetylation-Dependent degradation of glutamine synthetase via the thalidomide receptor cereblon","volume":"61","author":"Nguyen","year":"2016","journal-title":"Molecular Cell"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.bbrc.2010.01.094","article-title":"Transcriptional regulation of the human establishment of cohesion 1 homolog 2 gene","volume":"393","author":"Nishihara","year":"2010","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s41589-018-0055-y","article-title":"Plasticity in binding confers selectivity in ligand-induced protein degradation","volume":"14","author":"Nowak","year":"2018","journal-title":"Nature Chemical Biology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.pharmthera.2012.07.004","article-title":"The application and biology of immunomodulatory drugs (IMiDs) in cancer","volume":"136","author":"Pan","year":"2012","journal-title":"Pharmacology & Therapeutics"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.ajhg.2017.04.008","article-title":"GZF1 mutations expand the genetic heterogeneity of Larsen syndrome","volume":"100","author":"Patel","year":"2017","journal-title":"The American Journal of Human Genetics"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/nature16979","article-title":"Structural basis of lenalidomide-induced CK1\u03b1 degradation by the CRL4(CRBN) ubiquitin ligase","volume":"532","author":"Petzold","year":"2016","journal-title":"Nature"},{"key":"bib44","article-title":"R: A language and environment for statistical computing","volume-title":"R Foundation for Statistical Computing","author":"R Core Team","year":"2013","unstructured":"R Core Team. 2013. R: A language and environment for statistical computing. Vienna, Austria. R Foundation for Statistical Computing."},{"key":"bib45","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.cbpa.2017.05.016","article-title":"Targeted protein knockdown using small molecule degraders","volume":"39","author":"Raina","year":"2017","journal-title":"Current Opinion in Chemical Biology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Research"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1242\/dev.02457","article-title":"The murine homolog of SALL4, a causative gene in okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in Anorectal, heart, brain and kidney development","volume":"133","author":"Sakaki-Yumoto","year":"2006","journal-title":"Development"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1101\/gr.209643.116","article-title":"Multiparameter functional diversity of human C2H2 zinc finger proteins","volume":"26","author":"Schmitges","year":"2016","journal-title":"Genome Research"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1136\/jmedgenet-2016-104117","article-title":"A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family","volume":"54","author":"Sheereen","year":"2017","journal-title":"Journal of Medical Genetics"},{"key":"bib50","first-page":"194","volume-title":"Embryopathic Activity of Drugs, Biological Council Symposium","author":"Smith","year":"1965"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"311","DOI":"10.2165\/00003088-200443050-00004","article-title":"Clinical pharmacokinetics of thalidomide","volume":"43","author":"Teo","year":"2004","journal-title":"Clinical Pharmacokinetics"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/bdrc.21096","article-title":"Thalidomide-induced teratogenesis: history and mechanisms","volume":"105","author":"Vargesson","year":"2015","journal-title":"Birth Defects Research Part C: Embryo Today: Reviews"},{"key":"bib53","first-page":"107","article-title":"The thalidomide embryopathy in hybrid rabbits","volume":"48","author":"Vickers","year":"1967","journal-title":"British Journal of Experimental Pathology"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"E690","DOI":"10.1073\/pnas.1115485109","article-title":"Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin","volume":"109","author":"Zakeri","year":"2012","journal-title":"PNAS"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/38430\/elife-38430-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/38430\/elife-38430-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/38430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:58:58Z","timestamp":1697057938000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/38430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,1]]},"references-count":54,"alternative-id":["10.7554\/eLife.38430"],"URL":"https:\/\/doi.org\/10.7554\/elife.38430","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"uri","id":"https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD010416","asserted-by":"subject"},{"id-type":"uri","id":"https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD010417","asserted-by":"subject"},{"id-type":"uri","id":"https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD010418","asserted-by":"subject"},{"id-type":"uri","id":"https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD010420","asserted-by":"subject"},{"id-type":"uri","id":"https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD010428","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.38430.045","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.38430.044","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,1]]},"article-number":"e38430"}}