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

Neault, M.; Lebert-Ghali, C.-E.; Fournier, M.; Capdevielle, C.; Garfinkle, E. A. R.; Obermayer, A.; Cotton, A.; Boulay, K.; Sawchyn, C.; Nguyen, K. H.; Assaf, B.; Mercier, F. E.; Delisle, J.-S.; Drobetsky, E. A.; Hulea, L.; Shaw, T. I.; Zuber, J.; Gruber, T. A.; Melichar, H. J.; Mallette, F. A.

doi:10.1101/2022.12.16.520129

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bioRxiv · 10.1101/2022.12.16.520129

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

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Abstract

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.

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Neault, M., Lebert-Ghali, C.-E., Fournier, M., Capdevielle, C., Garfinkle, E. A. R., Obermayer, A., Cotton, A., Boulay, K., Sawchyn, C., Nguyen, K. H., Assaf, B., Mercier, F. E., Delisle, J.-S., Drobetsky, E. A., Hulea, L., Shaw, T. I., Zuber, J., Gruber, T. A., Melichar, H. J., Mallette, F. A.. 2022-12-19. CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to Navitoclax. https://doi.org/10.1101/2022.12.16.520129

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