TLX1/HOX11-mediated disruption of primary thymocyte differentiation prior to the CD4+CD8+ double-positive stage.
TLX1/HOX11-mediated disruption of primary thymocyte differentiation prior to the CD4+CD8+ double-positive stage.
复制标题
TLX1/HOX11 介导的 CD4 CD8 双阳性阶段之前原代胸腺细胞分化的破坏。
DOI：
10.1111/j.1365-2141.2005.05850.x
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发表时间：
2006
影响因子：
6.5
通讯作者：
Hawley,RobertG
中科院分区：
文献类型：
--
作者：
Owens,BronwynM;Hawley,TeresaS;Spain,LisaM;Kerkel,KristiA;Hawley,RobertG
TLX1/HOX11同源盒基因在 T 细胞急性淋巴细胞白血病 (T-ALL) 中经常通过 t(10;14)(q24;q11) 和 t(7;10)(q35;q24) 染色体易位或在不存在 10q24 细胞遗传学异常的情况下通过迄今未知的转录机制激活。几乎所有 TLX1+T-ALL 均表现出 CD4+CD8+ 双阳性 (DP) 表型。为了研究 TLX1 作为起始癌基因在 T-ALL 发病机制中的作用，我们评估了逆转录病毒载体引导的 TLX1 表达在胎儿胸腺器官培养物中小鼠和人类胸腺细胞分化过程中的后果。有趣的是，TLX1的强制表达破坏了小鼠胎肝前体细胞和人脐带血CD34+干细胞/祖细胞在DP胸腺细胞阶段之前的分化。尽管分化停滞与凋亡胸腺细胞百分比增加有关，但转基因 BCL2 的共表达只能部分绕过分化停滞。同源结构域第 51 位的不变天冬酰胺残基的突变（这是有效 DNA 结合所必需的）释放了该阻断，这与 TLX1 通过充当转录因子抑制胸腺细胞分化并促进 T 细胞肿瘤发生的观点一致。这些发现的相关性在激活 NOTCH1 突变和 TLX1+T-ALL 多步转化过程中涉及的其他遗传损伤的背景下进行了讨论。
TheTLX1/HOX11homeobox gene is frequently activated in T‐cell acute lymphoblastic leukaemia (T‐ALL) by the t(10;14)(q24;q11) and t(7;10)(q35;q24) chromosomal translocations or by as yet unknown transcriptional mechanisms in the absence of 10q24 cytogenetic abnormalities. Almost all TLX1+T‐ALLs exhibit a CD4+CD8+double‐positive (DP) phenotype. To investigate the role ofTLX1as an initiating oncogene in T‐ALL pathogenesis, we assessed the consequences of retroviral vector‐directedTLX1expression during the differentiation of murine and human thymocytes in fetal thymic organ cultures. Interestingly, enforced expression ofTLX1disrupted the differentiation of murine fetal liver precursors and human cord blood CD34+stem/progenitor cells prior to the DP thymocyte stage. Although differentiation arrest was associated with an increased percentage of apoptotic thymocytes, it could only be partially bypassed by coexpression of transgenicBCL2. Mutation of the invariant asparagine residue at position 51 of the homeodomain – which is required for efficient DNA binding – released the block, consistent with the notion that TLX1 inhibits thymocyte differentiation and promotes T‐cell oncogenesis by functioning as a transcription factor. The relevance of these findings is discussed in the context of activatingNOTCH1mutations and the other genetic lesions implicated in the multistep transformation process of TLX1+T‐ALL.