Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice (Retracted article. See vol. 78, pg. 6908, 2018)
Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice (Retracted article. See vol. 78, pg. 6908, 2018)
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DOI：
10.1158/0008-5472.can-05-1889
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Fusco, A
中科院分区：
文献类型：
--
作者：
Fedele, M;Fidanza, V;Fusco, A
HMGA1蛋白是染色质结构和基因控制的主要因素。它在肿瘤转化中起关键作用。实际上，HMGA1合成的阻塞可通过鼠转化逆转录病毒来阻止大鼠甲状腺细胞的转化，而在反义方向中携带HMGA1基因的腺病毒腺病病毒会诱导型型人体甲状腺癌细胞系中的凋亡细胞死亡，但在正常甲状腺正常甲状腺细胞中诱导。此外，体外和体内研究都确立了HMGA1基因的致癌作用。在这项研究中，为了在体内定义HMGA1功能，我们检查了破坏小鼠HMGA1基因的后果。 HMGA1-NULL等位基因的杂合子和纯合小鼠都表现出心脏肥大，这是由于HMGA1在心肌细胞生长调节中的直接作用。这些小鼠还出现了血液学恶性肿瘤，包括B细胞淋巴瘤和髓样肉芽肿性白血病。在RMGA1敲除脾组织中观察到的RAG1/2内切酶的B细胞膨胀和增加的表达可能是导致在这些肿瘤中观察到的异常IGH重排率的高率。因此，此处报告的数据表明HMGA1在心脏发育和生长中的关键作用，并揭示了该基因在血液系统恶性肿瘤中的抗四因素潜力。
The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in RMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies.