Hox genes:: From leukemia-to hematopoietic stem cell expansion
Hox genes:: From leukemia-to hematopoietic stem cell expansion
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DOI：
10.1196/annals.1349.014
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Humphries, RK
中科院分区：
文献类型：
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作者：
Abramovich, C;Pineault, N;Humphries, RK
Hox 基因显然与白血病有关；然而，不同旁系同源组的 Hox 基因之间的致白血病潜力的特异性以及同源结构域的作用均不清楚。我们单独测试了各种 NUP98-Hox 融合基因以及与 MEIS1 一起的致白血病潜力。所有测试的基因在体外的骨髓细胞中都具有显着的重叠效应。然而，并非所有的NUP98融合基因都形成强致白血病；但与MEIS1的过度表达一起，均诱发髓系白血病。这种现象也出现在仅含有相应 Hox 蛋白同源结构域的 NUP98 融合体中。然后，我们利用NUP98-HOXD13和NUP98-HOXA10的强大转化潜力来建立由早期骨髓祖细胞组成的白血病前期骨髓系，其具有广泛的体外自我更新能力、短期骨髓再生活性和自发白血病转化的低倾向。我们还表明MEIS1可以有效诱导它们转化为白血病干细胞，从而为白血病进展的研究提供了一种新的模型。与大多数测试的 Hox 基因的致白血病作用相反，HOXB4 能够增强造血干细胞的自我更新而不破坏正常分化。基于白血病基因HOXA9也可以扩增造血干细胞的发现，我们比较了NUP98-Hox融合体与HOXB4在体外触发HSC扩增的能力。我们的初步结果表明 HOXB4 的扩展潜力得以保留，甚至通过与 NUP98 融合而增强。此外，使用 Abd-B 样 Hox 融合基因可能会实现更大的扩增。
Hox genes are clearly implicated in leukemia; however, neither the specificity of the leukemogenic potential among Hox genes of different paralog groups nor the role of the homeodomain is clear. We tested the leukemogenic potential of various NUP98-Hox fusion genes alone and with MEIS1. All genes tested had a significant overlapping effect in bone marrow cells in vitro. However, not all formed strong leukemogenic NUP98 fusion genes; but together with overexpression of MEIS1, all induced myeloid leukemia. This phenomenon was also seen with NUP98 fusions containing only the homeodomain of the corresponding Hox protein. We then exploited the strong transforming potential of NUP98-HOXD13 and NUP98-HOXA10 to establish preleukemic myeloid lines composed of early myeloid progenitors With extensive in vitro self-renewal capacity, short-term myeloid repopulating activity, and low propensity for spontaneous leukemic conversion. We also showed that MEIS1 can efficiently induce their conversion to leukemic stem cells, thus providing a novel model for the study of leukemic progression. In contrast to the leukemogenic effect of most of the Hox genes tested, HOXB4 has the ability to increase the self-renewal of hematopoietic stem cells without disrupting normal differentiation. On the basis of the discovery that the leukemogenic gene HOXA9 can also expand hematopoietic stem cells, we compared the ability of NUP98-Hox fusions to that of HOXB4 to trigger HSC expansion in vitro. Our preliminary results indicate that the expanding potential of HOXB4 is retained and even augmented by fusion to NUP98. Moreover, even greater expansion may be possible using Abd-B-like Hox fusions genes.