Restoring a signaling pathway that is prevalent in fetal stem cells but dormant in adult ones may hold potential as an alterative treatment for T-cell acute lymphoblastic leukemia (T-ALL), an often-deadly type of blood cancer.
In a study published in Cell Stem Cell (November 2018), a TFRI-funded team led by Vancouver clinician-scientist Dr. Andrew Weng (BC Cancer) describes how they set about using mouse models of T-ALL from two different types of progenitor cells – fetal liver (FL) cells and adult bone marrow (BM) cells – to determine if leukemia had different biological properties at different stages of life.
“What we discovered is that fetal and adult leukemias behave differently and that these differences are primarily based on the inhibition or activation of two pathways: EZH2 and IGF1,” said Dr. Weng, the paper’s senior author.
According to Dr. Weng, NOTCH 1-driven autocrine IGF1 signalling is active in FL cells but restrained in adult BM cells due to a process known as EZH2-dependent H3K27 trimethylation. This fundamental biological difference has a huge impact on the aggressiveness of a leukemia as the scientists found that FL cells with active IGF1 signalling had reduced transplantability when compared to BM cells and had less leukemia stem cell activity.
This observation led them to search for ways to pharmacologically block EZH2-dependent H3K27 trimethylation to restore IGF1 signalling in adult cells, a process that yielded positive results in both mouse models and patient-derived xenografts.
“We found that enforced IGF1 signaling depletes leukemia stem cells in both mouse and human T-ALL,” said Dr. Weng. “These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer.”
Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity
Vincenzo Giambra, Samuel Gusscott, Deanne Gracias, Raymond Song, Sonya H. Lam, Patrizio Panelli, Kateryna Tyshchenko, Catherine E. Jenkins, Catherine Hoofd, Alireza Lorzadeh, Annaick Carles, Martin Hirst, Connie J. Eaves, and Andrew P. Weng
This study was partially funded by a Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation