13:00 Presentation "Hijacking the ubiquitin-proteasome system to expand stem cells"

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy to treat hematological disorders, but mainly limited by a number of matched donors.  Umbilical cord blood (UCB) is an attractive alternative, but each unit contains a limited number of HSCs. UM171, a small molecule, was shown to significantly expand the number of UCB hematopoietic stem and progenitor cells (HSPCs) in vitro, and the expanded cells are being tested in clinical trials with promising results. However, the molecular mechanism of UM171 was unknown.

 

Recently we discovered that UM171 triggers rapid degradation of the CoREST complex (RCOR1 and LSD1) to promote the expansion of HSPCs in vitro. However, the precise molecular mechanism behind the CoREST degradation was not known. Recent studies suggest that a new class of small molecules called molecular glues can promote the specific degradation of a target protein by modulating an E3 ubiquitin ligase. We hypothesized that UM171 could act as a molecular glue by modulating a ubiquitin ligase to promote the degradation of the CoREST complex. With a pooled CRISPR screen, we identified that Cul3KBTBD4 ubiquitin ligase was modulated by UM171 to promote the RCOR1/3 degradation.

 

These findings reveal CoREST as a novel regulator of HSC fate decisions and provide a mechanistic basis for UM171. On a broader front, our results indicate the possibility of targeting chromatin-associated CoREST complex, which opens new therapeutic applications for UM171.