Navarro Susana, Meza Nestor W, Quintana-Bustamante Oscar, Casado José A, Jacome Ariana, McAllister Kimberly, Puerto Silvia, Surrallés Jordi, Segovia José C, Bueren Juan A
Hematopoiesis and Gene Therapy Division, CIEMAT/Marcelino Botín Foundation, Avenida Complutense No. 22, 28040 Madrid, Spain.
Mol Ther. 2006 Oct;14(4):525-35. doi: 10.1016/j.ymthe.2006.05.018. Epub 2006 Jul 20.
We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation). In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells (HSCs), compared to wild-type HSCs. Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2(Delta27/Delta27) HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy.
我们研究了Brca2/Fancd1基因发生次等位基因突变（Brca2(Delta27/Delta27)突变）的小鼠的造血表型。与在其他范可尼贫血（FA）小鼠模型中的观察结果不同，在Brca2(Delta27/Delta27)小鼠中，无论幼年还是成年，造血集落形成细胞（CFC）数量均较少。此外，在Brca2(Delta27/Delta27)骨髓（BM）细胞中观察到高自发染色体不稳定性发生率，但在Brca2(+/Delta27)或Fanca(-/-) BM细胞中未观察到。尽管Brca2(Delta27/Delta27) CFC对电离辐射不敏感，但在接受照射的Brca2(Delta27/Delta27)小鼠中观察到非常严重的造血综合征。传统的BM竞争实验表明，与野生型造血干细胞（HSC）相比，Brca2(Delta27/Delta27)造血干细胞存在明显的再填充缺陷。此外，我们首次在DNA修复疾病模型中观察到，处于自然生理环境中的Brca2(Delta27/Delta27) HSC存在非常显著的增殖缺陷。将野生型HSC移植到未预处理的Brca2(Delta27/Delta27)受体中逐渐发生的再填充让人联想到在包括FA在内的许多遗传疾病中观察到的体细胞镶嵌现象。与Brca2(Delta27/Delta27)突变相关的造血表型表明，这种FA-D1小鼠模型将成为开发包括基因治疗在内的FA新疗法的重要工具。
