Biology subjects

Mercier, F. E.

Publications and source records attributed to Mercier, F. E..

2 recordsLinked to original sources

bioRxiv2024

Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators

Mechanisms driving the increase of cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed towards increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in leukemic cells. Public patient data confirmed expression levels of IRX5 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.

molecular biology↗

bioRxiv2022

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to Navitoclax

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive, uncurable blood cancer associated with poor therapeutic response and high mortality. We developed CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation, which occurs in human AMKL, increased the penetrance and decreased the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We uncover the dominant oncogenic properties of GLIS2, which trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of numerous BH3-only proteins, causing AMKL cell sensitivity to the BCL-2 inhibitor navitoclax both in vitro and in vivo, suggesting a novel therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL. Key pointsGLIS2 cooperates with activated Nras to promote the development of acute megakaryoblastic leukemia. CBFA2T3-GLIS2 and GLIS2 alter the expression of BCL2 family members rendering AMKL cells sensitive to navitoclax.

cancer biology↗