KBTBD4-mediated reduction of MYC is critical for hematopoietic stem cell expansion upon UM171 treatment

• UM171 mediates concomitant CoREST/MYC degradation, which requires CUL3^KBTBD4 ubiquitin ligase activation.

• Forced expression of MYC abolishes UM171-mediated HSC expansion and multilineage potential.

Ex vivo expansion of hematopoietic stem cells (HSCs) is gaining importance for cell and gene therapy, and requires a shift from dormancy state to activation and cycling. However, abnormal or excessive HSC activation results in reduced self-renewal ability and increased propensity for myeloid-biased differentiation. We now report that activation of the E3 ligase complex CRL3^KBTBD4 by UM171 not only induces epigenetic changes through CoREST1 degradation but also controls chromatin-bound master regulator of cell cycle entry and proliferative metabolism (MYC) levels to prevent excessive activation and maintain lympho-myeloid potential of expanded populations. Furthermore, reconstitution activity and multipotency of UM171-treated HSCs are specifically compromised when MYC levels are experimentally increased despite degradation of CoREST1.