Mouse Anti-Human SALL4 monoclonal antibody, clone JID770

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acrorenal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

The transcriptional factor SALL4, an important stem cell regulator, is expressed in hematopoietic stem cells and various malignancies, but its role in EGFR-mutated NSCLCs has not been studied yet. Here, we report that the expression of Sal-like protein 4 (SALL4), was significantly higher in EGFR mutated lung tumors than in non-tumor tissue. SALL4-high lung cancer patients had poorer prognosis after surgery than SALL4-low patients. The expression of SALL4 could be induced by the activation of EGFR through the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. The knockdown of SALL4 expression could suppress spheroid formation and the expression of lung cancer stem cell marker CD44. More interestingly, the knockdown of SALL4 expression could suppress the migration, invasion, and metastasis of the lung cancer cells and significantly increase the sensitivity of EGFR mutated cells to Erlotinib. These results suggest that SALL4 may be a novel potential therapeutic target for the diagnosis and treatment of lung cancer.