Thalidomide, which caused many birth defects, degrades transcription factor SALL4, necessary for fetal limb and organ development

Thalidomide first came on the U.S. market in the 1950s –– as a nonaddictive, nonbarbiturate sedative drug, having anti-emetic properties. Thus, it became widely used to treat morning sickness in pregnant women. Soon after the arrival of thalidomide on the market, some began to suspect the drug was causing severe birth defects. It wasn’t until 1961 that two independent convincing epidemiological studies confirmed that thalidomide was causative; this became known as the “largest preventable medical disaster in modern history”. Despite this tragedy, thalidomide (and its close derivatives, lenalidomide and pomalidomide), acting as immunomodulatory drugs, are still commonly used to treat several very serious clinical conditions such as multiple myeloma, and 5q-deletion associated myelodysplastic syndrome.

While a potentially successful treatment for certain malignancies, the molecular mechanisms of thalidomide teratogenicity (birth defect-causing), and many of its biological activities, remain elusive. However, recently it was shown that thalidomide and analogs exert their therapeutic effect by binding to the Cullin RING E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN, thereby enhancing degradation of pivotal key efficacy targets –– such as the zinc-finger transcription factors IKAROS, AIOLOS, and ZFP91.

Authors [see attached preprint] showed that immunomodulatory drugs disrupt a broad transcriptional network through the increaed degradation of several C2H2 [(Cysteine)2(Histidine)2; (Cys)2(His)2] zinc-finger transcription factors –– including SALL4 (member of the Spalt-like family of developmental transcription factors). Intriguingly, human genetic studies had shown that heterozygous loss-of-function (LOF) mutations in the SALL4 gene result in a developmental condition that mimics thalidomide-induced birth defects such as absence of thumbs, phocomelia (hands and/or feet attached close to the trunk, the limbs being grossly underdeveloped or absent –– a trait seen in many Vietnamese children exposed to high levels of Agent Orange), defects in ear and eye development, and congenital heart disease. Authors demonstrated that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits –– but not in rodents or fish –– which provides a mechanistic link for the species-specific pattern of pathogenesis that is seen with the thalidomide syndrome.

eLife 2o18; 7: e38430
COMMENT: It should be clarified that thalidomide in the United States was never approved for use in pregnant women. (MBG)

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