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

• Published in: Cell reports (Cambridge) 2023-09, Vol.42 (9), p.113084-113084, Article 113084
• Main Authors: Neault, Mathieu, Lebert-Ghali, Charles-Étienne, Fournier, Marilaine, Capdevielle, Caroline, Garfinkle, Elizabeth A.R., Obermayer, Alyssa, Cotton, Anitria, Boulay, Karine, Sawchyn, Christina, St-Amand, Sarah, Nguyen, Kamy H., Assaf, Béatrice, Mercier, François E., Delisle, Jean-Sébastien, Drobetsky, Elliot A., Hulea, Laura, Shaw, Timothy I., Zuber, Johannes, Gruber, Tanja A., Melichar, Heather J., Mallette, Frédérick A.
• Format: Article
• Language: English
• Subjects: acute megakaryoblastic leukemia; apoptosis; BCL2; CBFA2T3-GLIS2; ETO2-GLIS2; mouse model; navitoclax; pediatric cancer; Ras
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113084

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. [Display omitted] •Transplantation of CBFA2T3-GLIS2-expressing fetal liver cells causes AMKL in mice•GLIS2 cooperates with activated Nras to promote the development of AMKL•CBFA2T3-GLIS2 and GLIS2 alter the expression of BCL2 family members•CBFA2T3-GLIS2-dependent AMKL is sensitive to the BCL2 inhibitor navitoclax Using transcriptomic characterization of CBFA2T3-GLIS2-driven acute megakaryoblastic leukemia (AMKL) derived from a mosaic murine model of the disease, Neault et al. show a critical contribution of GLIS2 and activated RAS in promoting AMKL. CBFA2T3-GLIS2 upregulates the expression of the anti-apoptotic protein BCL2, and CBFA2T3-GLIS2-positive AMKL cells are sensitive to navitoclax.