Overexpression. of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion
Overexpression. of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion
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DOI：
10.1182/blood.v99.1.121
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Sauvageau, G
中科院分区：
文献类型：
--
作者：
Thorsteinsdottir, U;Mamo, A;Sauvageau, G
细胞遗传学、遗传学和功能研究已经证明了Hoxa9表达失调与急性髓性白血病（AML）之间的直接联系。Hoxa9在小鼠骨髓细胞中的过表达总是在3至10个月内导致AML，这表明在AML之前需要额外的遗传事件。为了进一步了解Hoxa9如何影响白血病前期的造血发育，我们设计了Hoxa9的过表达（1）使用逆转录病毒介导的基因转移在造血干细胞中并产生骨髓移植嵌合体，以及（2）使用转基因小鼠在淋巴细胞中。与对照组相比，Hoxa9转导细胞的受体在可移植的淋巴骨髓样长期再增殖细胞中增加了约15倍，表明这种癌基因赋予造血干细胞生长优势的能力。此外，Hoxa 9在更成熟的细胞中的过表达增强了粒细胞生成，并在前B细胞阶段部分阻断了B淋巴细胞生成，但对T淋巴发育没有可检测的影响。有趣的是，尽管Hoxa 9在T和B淋巴谱系中特异性高表达，但在超过18个月的观察期内，没有一只Hoxa 9转基因小鼠发生淋巴恶性肿瘤。
Cytogenetic, genetic, and functional studies have demonstrated a direct link between deregulated Hoxa9 expression and acute myeloid leukemia (AML). Hoxa9 overexpression in mouse bone marrow cells invariably leads to AML within 3 to 10 months, suggesting the requirement for additional genetic events prior to AML. To gain further insight into how Hoxa9 affects hematopoietic development at the preleukemic stage, we have engineered its overexpression (1) in hematopoietic stem cells using retrovirus-mediated gene transfer and generated bone marrow transplantation chimeras and (2) in lymphoid cells using transgenic mice. Compared with controls, recipients of Hoxa9-transduced cells had an about 15-fold increase in transplantable lymphomyeloid long-term repopulating cells, indicating the capacity for this oncogene to confer a growth advantage to hematopoietic stem cells.: In addition, overexpression of Hoxa9 in more mature cells enhanced granulopoiesis and partially blocked B lymphopoiesis at the pre-B-cell stage but had no detectable effect on T lymphoid development. Interestingly, despite specifically directing high expression of Hoxa9 in T and B lymphoid lineages, none of the Hoxa9transgenic mice developed lymphoid malignancies for the observation period of more than 18 months.