Cell of origin in radiation-induced premalignant thymocytes with differentiation capability in mice conditionally losing one Bcl11b allele
Cell of origin in radiation-induced premalignant thymocytes with differentiation capability in mice conditionally losing one Bcl11b allele
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DOI：
10.1111/cas.12193
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发表时间：
2013-08-01
期刊：
影响因子：
5.7
通讯作者：
Kominami, Ryo
中科院分区：
文献类型：
--
作者：
Go, Rieka;Hirose, Satoshi;Kominami, Ryo
Bcl 11b是一种单倍不足的肿瘤抑制因子，在10-16%的T细胞急性淋巴细胞白血病中发现了其突变或缺失。Bcl 11b（KO/+）杂合子小鼠易患胸腺淋巴瘤，这是一种T细胞急性淋巴母细胞白血病模型，当γ射线照射时，照射后的Bcl 11b（KO/+）小鼠在胸腺淋巴瘤发展之前产生克隆扩增或恶变前胸腺细胞。辐射诱导DNA损伤的细胞被认为是肿瘤的起源细胞;然而，哪种胸腺细胞是肿瘤细胞的起源仍然不清楚。在这项研究中，我们产生了Bcl 11b（flox/+）; Lck-Cre和Bcl 11b（flox/+）; CD 4-Cre小鼠;在前者中，一个Bcl 11b等位基因的丢失发生在未成熟的CD 4（-）CD 8（-）阶段的胸腺细胞中，而在后者中，丢失发生在更分化的CD 4（+）CD 8（+）双阳性阶段。我们研究了3戈伊γ射线照射后60天小鼠胸腺细胞的克隆扩增和分化。在Bcl 11b（flox/+）; Lck-Cre组中有一半（9/18）的胸腺在T细胞受体β（TCRb）位点显示有限的重排位点，表明克隆细胞扩增，但在Bcl 11b（flox/+）; CD 4-Cre组中没有。这表明癌前胸腺细胞的来源不是双阳性细胞，而是未成熟的胸腺细胞。有趣的是，这些癌前胸腺细胞在TCR α基因座的各个不同位点发生重排，大多数显示出TCR β和CD 8的更高表达，以及更分化的表型。这表明在癌前细胞中存在一个能够增殖并持续产生分化的胸腺细胞的未成熟细胞亚群。
Bcl11b is a haploinsufficient tumor suppressor, mutations or deletion of which has been found in 10-16% of T-cell acute lymphoblastic leukemias. Bcl11b(KO/+) heterozygous mice are susceptible to thymic lymphomas, a model of T-cell acute lymphoblastic leukemia, when gamma-irradiated, and irradiated Bcl11b(KO/+) mice generate clonally expanding or premalignant thymocytes before thymic lymphoma development. Cells with radiation-induced DNA damages are assumed to be the cells of origin in tumors; however, which thymocyte is the tumor cell origin remains obscure. In this study we generated Bcl11b(flox/+); Lck-Cre and Bcl11b(flox/+); CD4-Cre mice; in the former, loss of one Bcl11b allele occurs in thymocytes at the immature CD4(-)CD8(-) stage, whereas in the latter the loss occurs in the more differentiated CD4(+)CD8(+) double-positive stage. We examined clonal expansion and differentiation of thymocytes in mice 60 days after 3 Gy gamma-irradiation. Half (9/18) of the thymuses in the Bcl11b(flox/+); Lck-Cre group showed limited rearrangement sites at the T-cell receptor-beta (TCRb) locus, indicating clonal cell expansion, but none in the Bcl11b(flox/+); CD4-Cre group did. This indicates that the origin of the premalignant thymocytes is not in double-positive cells but immature thymocytes. Interestingly, those premalignant thymocytes underwent rearrangement at various different sites of the TCR alpha locus and the majority showed a higher expression of TCR beta and CD8, and more differentiated phenotypes. This suggests the existence of a subpopulation of immature cells within the premalignant cells that is capable of proliferating and continuously producing differentiated thymocytes.