UM171 Induces Stem Cell Expansion in High-Risk Leukemias, Myelodysplasias

The proprietary small molecule UM171 has the potential to create improved hematopoietic stem cell (HSC) therapies through efficient HSC expansion in patients with high-risk leukemias and myelodysplasias, according to a study published in Blood.

The study further elucidated the mechanism of action of UM171, which promotes degradation of the CoREST1 complex, or ELM2 domain-containing proteins, and reduces levels of chromatin-bound MYC by activating the CRL3^KBTBD4 E3 ubiquitin ligase, according to the authors, led by Jalila Chagraoui, PhD, of Maisonneuve-Rosemont Hospital in Canada.

“Our work emphasizes the importance of two interconnected determinants (epigenetic and metabolic) for achieving expansion of functional HSCs,” Dr. Chagraoui and colleagues wrote. “UM171-mediated CRL3^KBTBD4 potentiation not only preserves the epigenetic signature of HSCs through CoREST1 degradation, but also limits division rate, CD71 clearance, and protein synthesis, potentially through MYC reduction, thus ensuring their full regenerative potential.”

MYC reduction is critical for UM171-induced expansion and preservation of HSCs. While HSC expansion requires a shift from dormancy state to activation and cycling, excessive HSC activation results in reduced self-renewal and an increased propensity for myeloid-biased differentiation.

Dr. Chagraoui and colleagues evaluated UM171 in ex vivo human cell lines and in vivo NOD scid gamma mice. Due to high clonogenicity, they used OCI-AML1 cell lines to dissect the mode of action of UM171. At an optimal, nontoxic dose of 250 nM, most OCI-AML1 cells respond to UM171 treatment. The researchers determined that KBTBD4 is critical for both in vivo activity of UM171-expanded cells and UM171-induced MYC reduction.

The study also evaluated the effect of UM171 on RNA and protein synthesis and observed a “significant KBTBD4-dependent reduction” (30%) in 5-ethynyluridine labeling of nascent RNA in OCI-AML1 cells. UM171 also decreased the rate of protein synthesis in both OCIAML1 cells and CD34+ cells in a KBTBD4-dependent manner. Additionally, CD34+ cells exposed to UM171 showed an increase in lysosome content.

“A more comprehensive understanding of the molecular requirements for engineering healthy HSCs would greatly improve our ability to expand them without limiting their repopulating capacity and would be critical for future therapeutically relevant HSC manipulation,” the authors wrote.

Reference

Chagraoui J, Girard S, Mallinger L, Mayotte N, Tellechea MF, Sauvageau G. KBTBD4-mediated reduction of MYC is critical for hematopoietic stem cell expansion upon UM171 treatment. Blood. 2024. doi:10.1182/blood.2023021342