CBFA2T3-GLIS2依赖的儿童急性巨核细胞白血病由GLIS2驱动且对navitoclax敏感。
CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.
发表日期：2023 Sep 08
作者：
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
来源：
Stem Cell Research & Therapy
摘要：
儿童急性巨核细胞白血病（AMKL）是一种与治疗反应差和高死亡率相关的侵袭性血液癌症。本文描述了CBFA2T3-GLIS2驱动的AMKL小鼠模型的发展，这些模型再现了人类疾病的表型和转录特征。我们显示在人类AMKL中发生的一个激活Ras突变增加了CBF2AT3-GLIS2驱动的AMKL的穿透性并减少了其延迟期。CBFA2T3-GLIS2和GLIS2修饰相似的转录网络。我们鉴定了GLIS2的主导致癌特性，与致癌性Ras相互作用触发AMKL。我们发现CBFA2T3-GLIS2和GLIS2都改变了一些BH3-only蛋白的表达，导致AMKL细胞对BCL2抑制剂navitoclax在体外和体内都表现出敏感性，为患有CBFA2T3-GLIS2驱动AMKL的儿科患者提供了潜在的治疗选择。
版权所有 © 2023作者。由Elsevier Inc.出版。保留所有权利。
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.