Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg A M, Sauvageau G
Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Montréal, Québec, Canada H2W 1R7.
EMBO J. 1998 Jul 1;17(13):3714-25. doi: 10.1093/emboj/17.13.3714.
Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemic transformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and with Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study, we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 or Meis1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months when transplanted into syngenic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or the combination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 months post-transplantation. Similar results were obtained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA-binding partners in transformation of hemopoietic cells.
Hoxa9、Meis1和Pbx1编码含同源结构域的蛋白质，在小鼠和人类的白血病转化中均有涉及。已证实Hoxa9、Meis1和Pbx1蛋白可相互发生物理作用，因为Hoxa9能与Meis1以及Pbx1协同结合共有DNA序列，而无论有无DNA存在，Meis1和Pbx1均可形成异二聚体。在本研究中，我们试图确定Hoxa9是否能与Pbx1或Meis1协同转化造血细胞。经逆转录病毒工程改造后同时过表达Hoxa9和Meis1a的原代骨髓细胞，在移植到同基因小鼠体内后，不到3个月就诱发了依赖生长因子的寡克隆急性髓系白血病。相比之下，单独过表达Hoxa9、Meis1a或Pbx1b，或Hoxa9与Pbx1b的组合，在移植后6个月内均未能急性转化这些细胞。当对FDC-P1细胞进行工程改造使其过表达这些基因并移植到同基因受体体内时，也得到了类似结果。因此，这些研究证明了Hox家族的一个成员与其DNA结合伙伴之一在造血细胞转化过程中存在选择性协同作用。
