Acute loss of TET function results in aggressive myeloid cancer in mice.
Acute loss of TET function results in aggressive myeloid cancer in mice.
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DOI：
10.1038/ncomms10071
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发表时间：
2015-11-26
影响因子：
16.6
通讯作者：
Rao A
中科院分区：
文献类型：
--
作者：
An J;González-Avalos E;Chawla A;Jeong M;López-Moyado IF;Li W;Goodell MA;Chavez L;Ko M;Rao A
TET家族双加氧酶氧化DNA中的5-甲基胞嘧啶（5 mC），并在许多类型的癌症中发挥肿瘤抑制活性。即使在没有泰特编码区突变的情况下，泰特功能丧失也与癌症密切相关。在这里，我们表明，急性消除泰特功能诱导的快速发展的侵略性，完全渗透和细胞自主性骨髓白血病的小鼠，指出一个致病作用泰特功能丧失这种骨髓恶性肿瘤。表型和转录分析显示造血干/祖细胞分化异常，红细胞和淋巴细胞分化受损，髓系分化强烈，与DNA修饰变化仅轻度相关。我们还观察到磷酸-H2 AX的进行性积累和DNA损伤修复途径的强烈损伤，这表明泰特蛋白在维持基因组完整性中起关键作用。 已知泰特双加氧酶具有肿瘤抑制活性。在此，An等人显示Tet 2/Tet 3双条件突变小鼠发展为侵袭性髓性白血病，并表明在泰特功能丧失后，髓性白血病发生的主要驱动因素不是DNA甲基化增加，而是异常基因表达和DNA损伤反应和修复缺陷。
TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity. TET dioxygenases are known to have tumour suppressor activity. Here, An et al. show that Tet2/Tet3 double conditional mutant mice develop aggressive myeloid leukaemia, and suggest that rather than increased DNA methylation, aberrant gene expression and defects in DNA damage response and repair are the major drivers of myeloid leukaemogenesis upon TET loss-of-function.