Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice
Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice
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DOI：
10.1371/journal.pone.0051228
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发表时间：
2012-12-10
期刊：
影响因子：
3.7
通讯作者：
Darnay, Bryant G.
中科院分区：
文献类型：
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作者：
Lamothe, Betty;Lai, YunJu;Darnay, Bryant G.
先前对小鼠tgf - β活化激酶1 （TAK1）条件消融的研究表明，TAK1在造血干细胞、B细胞、T细胞、肝细胞、肠上皮细胞、角化细胞和各种组织的生存和/或发育中具有强制性作用，主要是因为这些细胞的凋亡敏感性增加。并暗示TAK1是nf - κ B和应激激酶途径的关键调节因子，因此是细胞存活的关键中介。与对TAK1作用的理解相反，我们报道了一个小鼠模型，在该模型中，髓系室中TAK1的缺失会引起克隆性骨髓单核细胞扩增、脾肿大、多器官浸润、基因组不稳定和侵袭性、致命性骨髓单核细胞白血病。与之前的报道不同，同时删除TNF受体1 （TNFR1）未能挽救这种严重的表型。我们发现，在我们的小鼠模型中，疾病的特征与人类慢性髓细胞白血病（CMML）转化为急性髓细胞白血病（AML）的特征相似。因此，我们在30例AML患者中发现13例TAK1缺失（43%），从而为TAK1在白血病发生中的作用提供了直接的遗传证据。
Previous studies of the conditional ablation of TGF-beta activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells' increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-kappa B and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1's role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1's role in leukemogenesis.