Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
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DOI：
10.1038/s41467-019-10510-8
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发表时间：
2019-07-02
影响因子：
16.6
通讯作者：
Weng, Andrew P.
中科院分区：
文献类型：
--
作者：
Kusakabe, Manabu;Sun, Ann Chong;Weng, Andrew P.
人类癌症的机制研究在很大程度上依赖于细胞系和小鼠模型，但分别受到体外适应和物种背景问题的限制。最近的努力利用了患者来源的异种移植物；然而，这些努力受到遗传背景可变、无法研究早期事件以及可用性/重复性的实际问题的阻碍。我们报告了一种有效的、可重复的T细胞白血病模型，在该模型中，慢病毒转导正常人脐带血产生了似乎与自然疾病难以区分的侵袭性白血病。我们利用这个合成模型来揭示癌基因诱导的HOXB激活的作用，这种激活在白血病细胞来源中起作用，并在已建立的肿瘤中持续存在，在那里它定义了一个新的患者亚群，与其他已知的基因亚型不同，临床结果很差。我们进一步证明，在人类T-ALL中，HOXB前部基因通过表观遗传机制被特异性地激活，并在白血病前期细胞和已建立的克隆中赋予生长优势。
Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.