Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease
Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease
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DOI：
10.1038/sj.emboj.7600521
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发表时间：
2005-01-26
期刊：
影响因子：
11.4
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Wang, J;Iwasaki, H;Korsmeyer, SJ
染色体易位融合的混合谱系白血病（MLL）基因与多个合作伙伴的典型急性白血病的婴儿以及治疗相关的白血病。我们利用条件性敲入策略来绕过MLL-CBP表达引起的胚胎致死性，并评估诱导的MLL-CBP表达对造血的直接影响。在激活MLL-CBP的几天内，融合蛋白选择性地扩增粒细胞/巨噬细胞祖细胞（GMP）并增强其自我更新/增殖。MLL-CBP改变了GMP的基因表达程序，上调了包括Hox a9在内的一部分基因。通过RNA干扰抑制Hox a9表达证明MLL-CBP需要Hox a9用于其增强的细胞扩增。在暴露于亚致死γ射线或N-乙基-N-亚硝基脲（ENU）后，MLL-CBP小鼠发生了骨髓单核细胞增生，并进展为致死性骨髓增生性疾病。这些代表了治疗诱导的急性粒单核细胞白血病/慢性粒单核细胞白血病/骨髓增生异常/骨髓增生性疾病的谱，与在具有t的人类中观察到的相似（11;16）。这种MLL-CBP治疗相关骨髓增生性疾病的模型证明了这种MLL融合对GMP细胞的选择性及其与协同突变一起启动白血病发生的能力。
Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.