Abstract
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.
Highlights
Thalidomide was first marketed in the 1950s as a nonaddictive, nonbarbiturate sedative with antiemetic properties, and was widely used to treat morning sickness in pregnant women
While other targets of thalidomide, such as CSNK1A1 for lenalidomide or GZF1, ZBTB39 for pomalidomide, may contribute to the pleiotropic developmental conditions observed upon thalidomide exposure, SALL4 is consistently degraded across all IMiDs and human geneticists associate heterozygous loss of SALL4 with human developmental syndromes that largely phenocopy thalidomide syndrome
From the targets degraded across IMiDs, IKZF1/3 have been shown to be non-causative for birth defects, RNF166 is a ubiquitin ligase involved in autophagy (Heath et al, 2016), and ZNF692 knock-out mice do not exhibit a teratogenic phenotype (International Mouse Phenotyping Consortium et al, 2016)
Summary
Thalidomide was first marketed in the 1950s as a nonaddictive, nonbarbiturate sedative with antiemetic properties, and was widely used to treat morning sickness in pregnant women. It was already known that mutations in the gene that produces SALL4 cause two conditions called Duane Radial Ray syndrome and Holt-Oram syndrome Both conditions can result in birth defects like those seen in babies exposed to thalidomide. IMiD target identification efforts have largely focused on elucidating the mechanism of therapeutic efficacy of these drugs in MM and del(5q)-MDS (Gandhi et al, 2014a; Kronke et al, 2015, 2014; Lu et al, 2014) These hematopoietic lineages may not express the specific proteins that are important in the developmental events disrupted by thalidomide during embryogenesis. In the absence of tractable animal models that closely resemble the human disease, we focused on human embryonic stem cells (hESC) as a model system that more likely expresses proteins relevant to embryo development, and set out to investigate the effects of thalidomide in this developmental context
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