2020
DOI: 10.1038/s41598-020-59542-x
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Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

Abstract: exposure to thalidomide during a critical window of development results in limb defects in humans and non-human primates while mice and rats are refractory to these effects. Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phe… Show more

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Cited by 30 publications
(23 citation statements)
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“…[12][13][14][15][16][17] Molecular insights into the mechanism of action of immunomodulatory drugs in multiple myeloma (MM) and myelodysplastic syndrome with deletion of chromosome 5q accelerated the identification of novel cereblon neosubstrates [14][15][16][17] and laid out a solid foundation for the discovery and development of next-generation cereblon modulators. Recently, a number of novel neosubstrates of IMiDs including ZFP91, SALL4 and WIZ were discovered, [18][19][20][21][22] and several novel cereblon modulators such as CC-122, CC-220 and CC-885 targeting well-established or novel cereblon neosubstrates, were developed to treat various hematological malignancies. [5][6][7] Although several promising therapies have been developed for AML that target specific genetic and epigenetic mutations [23][24][25] , effective options for patients with poor risk cytogenetic features, or relapsed and refractory disease are still needed.…”
Section: Clinical Trial Registration Information (If Any)mentioning
confidence: 99%
“…[12][13][14][15][16][17] Molecular insights into the mechanism of action of immunomodulatory drugs in multiple myeloma (MM) and myelodysplastic syndrome with deletion of chromosome 5q accelerated the identification of novel cereblon neosubstrates [14][15][16][17] and laid out a solid foundation for the discovery and development of next-generation cereblon modulators. Recently, a number of novel neosubstrates of IMiDs including ZFP91, SALL4 and WIZ were discovered, [18][19][20][21][22] and several novel cereblon modulators such as CC-122, CC-220 and CC-885 targeting well-established or novel cereblon neosubstrates, were developed to treat various hematological malignancies. [5][6][7] Although several promising therapies have been developed for AML that target specific genetic and epigenetic mutations [23][24][25] , effective options for patients with poor risk cytogenetic features, or relapsed and refractory disease are still needed.…”
Section: Clinical Trial Registration Information (If Any)mentioning
confidence: 99%
“…When examined in comparison with such datasets, the gastruloids appear to be able to distinguish between known teratogens (such as valproic acid and retinoic acid) and those that are less teratogenic (ibuprofen) or non-teratogenic (penicillin G) [27–33]. They are even able to recapitulate known species-specific sensitivities such as the human-specific effect of thalidomide [3, 4, 34] and can highlight subtle changes in developmental gene expression (bosentan, thalidomide, phenytoin).…”
Section: Discussionmentioning
confidence: 99%
“…No reuse allowed without permission. [3,4,34] and can highlight subtle changes in developmental gene expression (bosentan, thalidomide, phenytoin).…”
Section: Discussionmentioning
confidence: 99%
“…Notably, the CRBN substitution V388I eliminates thalidomide-mediated interaction with IKZF1 as well as with protein kinase CK1α ( Gemechu et al, 2018 ; Asatsuma-Okumura et al, 2020 ). Furthermore, a recent study using human induced pluripotent stem cells demonstrated that CRBN V388I mutation abolished thalidomide-induced degradation of SALL4, and that this involved a specific interaction with SALL4 416 glycine (G416) whose mutation (G416A), likewise abrogated SALL4 breakdown ( Belair et al, 2020 ). Such studies provide an insight as to how select actions of thalidomide and clinical analogs are mediated via CRBN, but have yet to fully explain the development of teratogenicity whose resistance in rodents remains enigmatic ( Vargesson, 2015 , 2019 ; Asatsuma-Okumura et al, 2020 ).…”
Section: Immunomodulatory Imide Drugs (Imids)mentioning
confidence: 99%