The stem cell–supporting small molecule UM171 triggers Cul3-KBTBD4–mediated degradation of ELM2 domain–harboring proteins

Ex vivo expansion of hematopoietic stem cells (HSCs) is gaining in 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 CRL3KBTBD4 by UM171 not only induces epigenetic changes through CoREST1 degradation but also controls chromatin bound MYC levels to prevent excessive activation and maintain lympho-myeloid potential of expanded populations. Furthermore, reconstitution activity and multipotency of UM171-treated HSC is specifically compromised when MYC levels are experimentally increased despite degradation of CoREST1.

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UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease

Liu,

Klatt,

Zhou

et al. 2024

Blood Advances

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Hematopoietic stem cell transplantation with lentiviral vector (LVV) transduced autologous cells has proven an effective therapeutic strategy for sickle cell disease (SCD). However, ex vivo culture or proliferative stress associated with in vivo reconstitution may amplify any underlying genetic risk of leukemia. We aimed to minimize culture-induced stress and reduce genomic damage during ex vivo culture, enhance stem cell fitness and reconstitution of SCD CD34+ cells transduced with BCL11A shmiR-encoding LVV currently in clinical trials (NCT NCT03282656). UM171, a pyrimidoindole derivative can expand normal hematopoietic stem cells (HSCs) during in vitro culture and has been shown to be safe and effective in clinical trials using umbilical cord blood (NCT02668315). We examined the effect of UM171 during ex vivo LVV transduction of SCD HSCs. Culture of SCD CD34+ HSCs with UM171 during transduction reduced DNA damage and reactive oxygen species (ROS), decreased apoptosis, and was associated with increased numbers of immunophenotypically defined long-term HSCs. UM171 increased the engraftment of LVV transduced human HSCs in immunodeficient mice and barcode tracing revealed increased clonal diversity of engrafting cells. In competitive transplantation assays, analysis of BM showed that cells transduced in the presence of UM171 consistently outcompeted those transduced under control conditions. In summary, exposure of SCD peripheral blood CD34+ cells to UM171 during LVV transduction enhances stem cell fitness. These findings suggest manufacturing of genetically modified HSCs in the presence of UM171 may improve efficacy, safety and sustainability of gene therapy utilizing ex vivo approaches.

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The stem cell–supporting small molecule UM171 triggers Cul3-KBTBD4–mediated degradation of ELM2 domain–harboring proteins

Cited by 3 publications

References 31 publications

Ex vivo hematopoietic stem cell expansion technologies: recent progress, applications, and open questions

Ex vivo hematopoietic stem cell expansion technologies: recent progress, applications, and open questions

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

UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease

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