IRIC - Institute for Research in Immunology and Cancer

Published on January 29, 2024

The ex vivo expansion of hematopoietic stem cells (HSCs), an important advance for cell-based therapies, can lead to replicative and metabolic stresses; much as aging does. In their efforts to identify the best strategies for HSC expansion, the team led by Guy Sauvageau, Director of IRIC’s Molecular Genetics of Stem Cells Research Unit, has been investigating the molecular mechanisms induced by the UM171 molecule, which was jointly discovered in 2014 by his laboratory and the team led by Anne Marinier, Director of IRIC’s Drug Discovery Unit, and enables the ex vivo expansion of HSC derived from umbilical cord blood. Their most recent study, led by researcher Jalila Chagraoui and published in the journal Blood, reports that the UM171 molecule preserves HSCs from cell culture-induced stress by modulating the activity of the MYC protein.

Reducing MYC levels to reduce stress

Through its binding to a number of genes, MYC is involved in a variety of cellular processes, from cell cycle control to metabolism and self-renewal. Work in the Sauvageau laboratory has shown that MYC activity is reduced in cells treated with the molecule UM171. This effect requires the adaptor protein KBTBD4, which leads to the degradation of MYC, thus reducing its binding to chromatin. By adjusting the programs driven by MYC, UM171 helps to limit the exposure of HSCs to various stresses and preserve their capacities. The team also observed that forced MYC expression compromises the regenerative potential of UM171-expanded HSCs.

A dual role induced by UM171 for KBTBD4

Another mechanism involving KBTBD4 was recently uncovered by the Sauvageau laboratory: its activation by UM171 helps maintain the epigenetic landscape required to preserve HSC properties during ex vivo culture. Thus, UM171 acts on KBTBD4 to mediate both epigenetic and metabolic determinants that make the expansion of functional HSCs possible.

A thorough understanding of the molecular requirements to expand healthy HSCs will enable their development without limiting their regenerative capacities. The present work will contribute to improving the manipulation of HSCs for therapeutic purposes.

Cited study

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 Jan 11:blood.2023021342. doi: 10.1182/blood.2023021342. Epub ahead of print. PMID: 38207291.