Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma
Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma
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DOI：
10.1182/blood-2005-04-1447
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发表时间：
2005-11-15
期刊：
影响因子：
20.3
通讯作者：
Liu, PP
中科院分区：
文献类型：
--
作者：
Kundu, M;Compton, S;Liu, PP
影响RUNX 1和CBFB的染色体重排在急性白血病中很常见。这些突变导致融合蛋白的表达，其显性负性地抑制Runt相关转录因子1（RUNX）/核心结合因子β（CBF β）复合物的正常功能。此外，在急性髓性白血病（AML）的散发病例中发现了Runt相关转录因子1（RUNX 1）的功能缺失突变，并与具有发展AML倾向的家族性血小板疾病（FPD/AML）相关。为了检验RUNX 1基因剂量减少可能是白血病发展中的关键事件这一假设，我们用N-乙基-N-亚硝基脲（ENU）处理了由Runx 1（lacZ/lacZ）胚胎干（ES）细胞产生的嵌合小鼠，这些细胞具有Runx 1基因的纯合破坏。我们观察到Runx 1（lacZ/lacZ）与野生型嵌合体相比，T淋巴母细胞淋巴瘤的发病率增加，并证实肿瘤是ES细胞来源的。因此，我们的研究结果表明，Runx 1的缺陷确实可以使小鼠容易患造血系统恶性肿瘤。
Chromosomal rearrangements affecting RUNX1 and CBFB are common in acute leukemias. These mutations result in the expression of fusion proteins that act dominant-negatively to suppress the normal function of the Runt-related transcription factor 1 (RUNX)/core binding factor beta (CBF beta) complexes. In addition, loss-of-function mutations in Runt-related transcription factor 1 (RUNX1) have been identified in sporadic cases of acute myeloid leukemia (AML) and in association with the familial platelet disorder with propensity to develop AML (FPD/AML). In order to examine the hypothesis that decreased gene dosage of RUNX1 may be a critical event in the development of leukemia, we treated chimeric mice generated from Runx1(lacZ/lacZ) embryonic stem (ES) cells that have homozygous disruption of the Runx1 gene with N-ethyl-N-nitrosourea (ENU). We observed an increased incidence of T-lymphoblastic lymphoma in Runx1(lacZ/lacZ) compared with wildtype chimeras and confirmed that the tumors were of ES-cell origin. Our results therefore suggest that deficiency of Runx1 can indeed predispose mice to hematopoietic malignancies.