Whelan J T, Ludwig D L, Bertrand F E
Department of Microbiology and Immunology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Leukemia. 2008 Jun;22(6):1161-9. doi: 10.1038/leu.2008.57. Epub 2008 Mar 13.
The homeobox (Hox) gene family encodes a group of transcription factors preferentially expressed during embryonic development and hematopoiesis. Deregulation of Hox gene expression is frequently associated with acute leukemia. HoxA9 is the most commonly overexpressed Hox gene in acute leukemia. However, little is known regarding specific pathways regulated by HoxA9 that promote the growth and survival of leukemic cells. We have generated a conditional model of HoxA9 activity in the stromal cell dependent, HoxA9 negative, pre-B-cell line B-lineage-2 (BLIN-2). Conditional HoxA9 activation in BLIN-2 resulted in increased proliferation in the presence and absence of stromal cell support. Stimulation of HoxA9 activity resulted in increased expression of the c-Myb transcription factor and induction of insulin-like growth factor-1 receptor (IGF-1R) surface expression. HoxA9-mediated proliferative effects in BLIN-2 cells were abrogated when the cells were treated with specific IGF-1R tyrosine kinase inhibitors or with an IGF-1R mAb (A12). IGF-1R expression correlated with endogenous HoxA9 expression in a small panel of mixed lineage leukemia (MLL)/AF4 cell lines. siRNA knockdown of endogenous HoxA9 expression in the MLL/AF4-positive cell line RS4;11 resulted in loss of IGF-1R expression. These data indicate that HoxA9 overexpression induces IGF-1R expression and subsequently promotes leukemic cell growth.
同源框（Hox）基因家族编码一组转录因子，这些转录因子在胚胎发育和造血过程中优先表达。Hox基因表达失调常与急性白血病相关。HoxA9是急性白血病中最常过度表达的Hox基因。然而，关于HoxA9调控促进白血病细胞生长和存活的特定途径，我们知之甚少。我们在依赖基质细胞、HoxA9阴性的前B细胞系B谱系-2（BLIN-2）中构建了HoxA9活性的条件模型。在BLIN-2中条件性激活HoxA9导致在有和没有基质细胞支持的情况下增殖增加。刺激HoxA9活性导致c-Myb转录因子表达增加以及胰岛素样生长因子-1受体（IGF-1R）表面表达的诱导。当用特异性IGF-1R酪氨酸激酶抑制剂或IGF-1R单克隆抗体（A12）处理细胞时，HoxA9介导的BLIN-2细胞增殖效应被消除。在一小部分混合谱系白血病（MLL）/AF4细胞系中，IGF-1R表达与内源性HoxA9表达相关。在MLL/AF4阳性细胞系RS4;11中，通过小干扰RNA（siRNA）敲低内源性HoxA9表达导致IGF-1R表达丧失。这些数据表明HoxA9过表达诱导IGF-1R表达，随后促进白血病细胞生长。
