Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin
Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin
复制标题
Id1 在 MLL-AF9 驱动的白血病中基于细胞来源的不同作用。
DOI：
10.1182/blood-2015-11-677708
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发表时间：
2016-05-12
期刊：
影响因子：
20.3
通讯作者：
Wang, Lan
中科院分区：
文献类型：
--
作者：
Man, Na;Sun, Xiao-Jian;Wang, Lan
DNA结合抑制剂1 （Inhibitor of DNA binding 1, Id1）是一种E蛋白抑制剂，Id1在急性髓性白血病（AML）患者中过表达。为了确定Id1对白血病发生的影响，我们在野生型、Id1（-/-）、p21（-/-）或Id1(-/-)p21（-/-）小鼠的胎肝（FL）细胞或骨髓（BM）细胞中表达MLL-AF9，并将其移植到同基因受体小鼠中。我们发现，虽然接受mll - af9转导的FL或BM细胞的小鼠会发生AML，但Id1的缺失显著延长了接受FL细胞的小鼠的中位生存期，但加速了BM细胞受体的白血病发生。在两种模型中，Id1靶基因Cdkn1a （p21）的缺失可以挽救Id1缺失的影响，这表明Cdkn1a是Id1在白血病发生中的关键靶点。有研究表明，FL移植模型模拟人类胎儿源性（婴儿）MLL融合蛋白（FP）驱动的白血病，而BM移植模型类似于出生后MLL白血病；事实上，对MLL-FP（+）白血病患者临床样本的分析表明，前者的Id1表达升高，后者的MLL-FP(+) AML的Id1表达降低。我们的研究结果表明，Id1可能是婴儿mll - af9驱动白血病的潜在治疗靶点。
Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone marrow (BM) cells isolated from wild-type, Id1(-/-), p21(-/-), or Id1(-/-)p21(-/-) mice, and transplanted them into syngeneic recipient mice. We found that although mice receiving MLL-AF9-transduced FL or BM cells develop AML, loss of Id1 significantly prolonged the median survival of mice receiving FL cells but accelerated leukemogenesis in recipients of BM cells. Deletion of Cdkn1a (p21), an Id1 target gene, can rescue the effect of Id1 loss in both models, suggesting that Cdkn1a is a critical target of Id1 in leukemogenesis. It has been suggested that the FL transplant model mimics human fetal-origin (infant) MLL fusion protein (FP)-driven leukemia, whereas the BM transplantation model resembles postnatal MLL leukemia; in fact, the analysis of clinical samples from patients with MLL-FP(+) leukemia showed that Id1 expression is elevated in the former and reduced in the latter type of MLL-FP(+) AML. Our findings suggest that Id1 could be a potential therapeutic target for infant MLL-AF9-driven leukemia.