Sal-like protein 4 (SALL4) (SALL4)

Sal-like protein 4 (SALL4) is a zinc-finger transcription factor that plays a pivotal role in maintaining the pluripotency and self-renewal of embryonic stem cells (UniProt Q9UJQ4). While its expression is largely restricted to embryonic development and specific adult niches such as germ cells and hematopoietic stem cells, it is frequently reactivated in various malignancies, including hepatocellular carcinoma, acute myeloid leukemia, and germ cell tumors (PMID: 23770622). In these oncogenic contexts, SALL4 promotes tumor cell survival, proliferation, and chemoresistance. SALL4 has gained significant clinical attention as a "neo-substrate" for immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide. These drugs act as molecular glues that facilitate the recruitment of SALL4 to the Cereblon (CRBN) E3 ubiquitin ligase complex, leading to its ubiquitination and subsequent proteasomal degradation (PMID: 30061385). While this degradation is responsible for the therapeutic efficacy in some cancers, it is also the primary mechanism underlying the well-documented teratogenic effects of thalidomide. Consequently, SALL4 is both a high-priority therapeutic target in oncology and a major safety concern in drug development.

Other names

Sal-like 4Zinc finger protein SALL4HSAL4Spalt-like transcription factor 4

Induction of proteasomal degradation via the CRL4-CRBN E3 ubiquitin ligase complex (molecular glue mechanism); experimental RNA interference (siRNA) or antisense oligonucleotides (ASOs) targeting the mRNA transcript.