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

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of 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 that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Mathieu Neault, Charles-Étienne Lebert-Ghali, Marilaine Fournier, Caroline Capdevielle, Elizabeth A R Garfinkle, Alyssa Obermayer, Anitria Cotton, Karine Boulay, Christina Sawchyn, Sarah St-Amand, Kamy H Nguyen, Béatrice Assaf, François E Mercier, Jean-Sébastien Delisle, Elliot A Drobetsky, Laura Hulea, Timothy I Shaw, Johannes Zuber, Tanja A Gruber, Heather J Melichar, Frédérick A Mallette. CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax. Cell reports. 2023 Sep 26;42(9):113084

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PMID: 37716355

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