Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma
Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma
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DOI：
10.1182/blood-2005-07-3013
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发表时间：
2006-03-15
期刊：
影响因子：
20.3
通讯作者：
Aplan, PD
中科院分区：
文献类型：
--
作者：
Lin, YW;Nichols, RA;Aplan, PD
NOTCH1在人类前体T淋巴细胞白血病/淋巴瘤(Pre-T-LBL)中经常发生突变。在目前的研究中，我们发现来自SCL/LMO1、OLIG2/LMO1、OLIG2、LMO1、NUP98/Hoxd13和p27(-/-)/Smad3(+/-)小鼠的19个细胞系中的13个和49个原发肿瘤中的29个在异二聚化(HD)或谷氨酸/丝氨酸/苏氨酸(PEST)结构域中存在Notch1突变，但不同时存在这两种突变。临床健康的5周龄SCL/LMO1小鼠的胸腺细胞没有Notch1突变，而8-12周龄的临床健康SCL/LMO1小鼠的胸腺细胞在移植到裸鼠体内后有Notch1突变并形成肿瘤。值得注意的是，我们鉴定的所有HD结构域突变都是单碱基替换，而所有PEST结构域突变都是插入或缺失，其中一半映射到2个突变“热点”中的1个。综上所述，这些发现表明Notch1突变是非常频繁的事件，在白血病转化过程中相对较早地获得，对白血病细胞的生长很重要。
NOTCH1 is frequently mutated in human precursor T-cell lymphoblastic leukemia/ lymphoma (pre-T LBL). In the current study, we found that 13 of 19 cell lines and 29 of 49 primary tumors from SCL/LMO1, OLIG2/LMO1, OLIG2, LMO1, NUP98/ HOXD13, and p27(-/-)/SMAD3(+/-) mice had Notch1 mutations in either the heterodimerization (HD) or the glutamic acid/serine/threonine (PEST) domain but not both. Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks did not have Notch1 mutations, whereas thymocytes from clinically healthy SCL/LMO1 mice aged 8 to 12 weeks did have Notch1 mutations and formed tumors upon transplantation into nude mice. Remarkably, all of the HD domain mutations that we identified were single-base substitutions, whereas all of the PEST domain mutations were insertions or deletions, half of which mapped to 1 of 2 mutational "hot spots." Taken together, these findings indicate that Notch1 mutations are very frequent events that are acquired relatively early in the process of leukemic transformation and are important for leukemic cell growth.