Heuser Michael, Sly Laura M, Argiropoulos Bob, Kuchenbauer Florian, Lai Courteney, Weng Andrew, Leung Malina, Lin Grace, Brookes Christy, Fung Stephen, Valk Peter J, Delwel Ruud, Löwenberg Bob, Krystal Gerald, Humphries R Keith
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3 Canada.
Blood. 2009 Nov 5;114(19):3983-93. doi: 10.1182/blood-2009-06-227603. Epub 2009 Aug 10.
Although the cancer stem cell (CSC) concept implies that CSCs are rare, recent reports suggest that CSCs may be frequent in some cancers. We hypothesized that the proportion of leukemia stem cells would vary as a function of the number of dysregulated pathways. Constitutive expression of MN1 served as a 1-oncogene model, and coexpression of MN1 and a HOX gene served as a 2-oncogene model. Leukemia-initiating cell (LIC) number and in vitro expansion potential of LICs were functionally assessed by limiting dilution analyses. LIC expansion potential was 132-fold increased in the 2- compared with the 1-oncogene model, although phenotypically, both leukemias were similar. The 2-oncogene model was characterized by granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity and activated STAT/ERK signaling. GM-CSF hypersensitivity of the 2-oncogene model (MN1/HOXA9) was lost in Stat5b(-/-) cells, and the LIC expansion potential was reduced by 86- and 28-fold in Stat5b(-/-) and Stat1(-/-) cells, respectively. Interestingly, in 201 acute myeloid leukemia (AML) patients, coexpression of MN1 and HOXA9 was restricted to patients with the poorest prognosis and was associated with highly active STAT signaling. Our data demonstrate the functional heterogeneity of LICs and show that STAT signaling is critical for leukemia stem cell self-renewal in MN1- and HOXA9-expressing leukemias.
尽管癌症干细胞（CSC）概念意味着CSC罕见，但最近的报告表明CSC在某些癌症中可能很常见。我们假设白血病干细胞的比例会随着失调通路数量的变化而变化。MN1的组成型表达作为单癌基因模型，MN1与HOX基因的共表达作为双癌基因模型。通过有限稀释分析对白血病起始细胞（LIC）数量和LIC的体外扩增潜力进行功能评估。与单癌基因模型相比，双癌基因模型中LIC的扩增潜力增加了132倍，尽管在表型上，两种白血病相似。双癌基因模型的特征是对粒细胞-巨噬细胞集落刺激因子（GM-CSF）超敏以及STAT/ERK信号激活。双癌基因模型（MN1/HOXA9）的GM-CSF超敏性在Stat5b（-/-）细胞中丧失，并且在Stat5b（-/-）和Stat1（-/-）细胞中，LIC的扩增潜力分别降低了86倍和28倍。有趣的是，在201例急性髓系白血病（AML）患者中，MN1和HOXA9的共表达仅限于预后最差的患者，并且与高活性STAT信号相关。我们的数据证明了LIC的功能异质性，并表明STAT信号对于表达MN1和HOXA9的白血病中白血病干细胞的自我更新至关重要。
