5-10% of human acute leukemias carry chromosomal translocations involving the mixed lineage leukemia (MLL) gene that result in the expression of chimeric protein fusing MLL to >80 different partners of which AF4, ENL and AF9 are the most prevalent. In contrast to many other leukemia-associated mutations, several MLL-fusions are powerful oncogenes that transform hematopoietic stem cells but also more committed progenitor cells. Here, I review different approaches that were used to express MLL fusions in the murine hematopoietic system which often, but not always, resulted in highly penetrant and transplantable leukemias that closely phenocopied the human disease. Due to its simple and reliable nature, reconstitution of irradiated mice with bone marrow cells retrovirally expressing the MLL-AF9 fusion became the most frequently in vivo model to study the biology of acute myeloid leukemia (AML). I review some of the most influential studies that used this model to dissect critical protein interactions, the impact of epigenetic regulators, microRNAs and microenvironment-dependent signals for MLL fusion-driven leukemia. In addition, I highlight studies that used this model for shRNA- or genome editing-based screens for cellular vulnerabilities that allowed to identify novel therapeutic targets of which some entered clinical trials. Finally, I discuss some inherent characteristics of the widely used mouse model based on retroviral expression of the MLL-AF9 fusion that can limit general conclusions for the biology of AML. This article is part of a Special Issue entitled: The MLL family of proteins in normal development and disease edited by Thomas A Milne.

中文翻译：

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从MLL融合基因驱动的急性白血病的小鼠模型中学习。

5-10％的人类急性白血病携带涉及混合谱系白血病（MLL）基因的染色体易位，从而导致融合蛋白的表达与MLL融合至> 80个不同伴侣，其中AF4，ENL和AF9最常见。与许多其他与白血病相关的突变相反，几种MLL融合是强大的致癌基因，既可以转化造血干细胞，也可以转化为更祖细胞。在这里，我回顾了用于在小鼠造血系统中表达MLL融合蛋白的不同方法，这些方法经常（但并非总是）导致高度渗透性和可移植性白血病，这些白血病紧密地表象人类疾病。由于其简单可靠的特性，逆转录表达MLL-AF9融合蛋白的骨髓细胞对辐射小鼠的重组成为研究急性髓样白血病（AML）生物学的最常见的体内模型。我回顾了一些最有影响力的研究，这些研究使用该模型来剖析重要的蛋白质相互作用，表观遗传调控因子，microRNA和依赖微环境的信号对MLL融合驱动的白血病的影响。此外，我重点介绍了使用该模型进行基于shRNA或基因组编辑的筛查细胞脆弱性的研究，这些筛查可确定一些新的治疗靶标，其中一些已进入临床试验。最后，我讨论了基于MLL-AF9融合蛋白的逆转录病毒表达而广泛使用的小鼠模型的某些固有特征，这些特征可能会限制AML生物学的一般结论。