Chibon Frédéric, Mariani Odette, Derré Josette, Mairal Aline, Coindre Jean-Michel, Guillou Louis, Sastre Xavier, Pédeutour Florence, Aurias Alain
INSERM U509, Molecular Pathology of Cancers, Institut Curie, Paris, France.
Genes Chromosomes Cancer. 2004 May;40(1):32-7. doi: 10.1002/gcc.20012.
Malignant fibrous histiocytomas (MFHs) are aggressive tumors without any definable line of differentiation. We recently demonstrated that about 20% of them are characterized by high-level amplifications of the 12q14-q15 chromosome region, associated with either 1p32 or 6q23 band amplification. This genetic finding, very similar to that in well-differentiated liposarcomas, strongly suggests that these tumors actually correspond to undifferentiated liposarcomas. It also suggests that the lack of differentiation could be the consequence of amplification of target genes localized in the 1p32 or 6q23 bands. We report here the characterization by array CGH of the 6q23 minimal region of amplification. Our findings demonstrate that amplification and overexpression of ASK1 (MAP3K5), a gene localized in the 6q23 band and encoding a mitogen-activated protein kinase kinase kinase of the JNK-MAPK signaling pathway, could inhibit the adipocytic differentiation process of the tumor cells. Treatment of a cell line with specific inhibitors of ASK1 protein resulted in the bypass of the differentiation block and induction of a strong adipocytic differentiation. These observations indicate that ASK1 is a target for new therapeutic management of these aggressive tumors.
恶性纤维组织细胞瘤（MFH）是一种侵袭性肿瘤，没有任何明确的分化谱系。我们最近证明，其中约20%的肿瘤具有12q14-q15染色体区域的高水平扩增，与1p32或6q23带扩增相关。这一遗传学发现与高分化脂肪肉瘤非常相似，强烈提示这些肿瘤实际上相当于未分化脂肪肉瘤。这也表明缺乏分化可能是位于1p32或6q23带的靶基因扩增的结果。我们在此报告通过阵列比较基因组杂交（array CGH）对6q23最小扩增区域的特征分析。我们的研究结果表明，ASK1（MAP3K5）基因的扩增和过表达可抑制肿瘤细胞的脂肪细胞分化过程，ASK1基因位于6q23带，编码JNK-MAPK信号通路的丝裂原活化蛋白激酶激酶激酶。用ASK1蛋白特异性抑制剂处理细胞系导致分化阻滞的解除并诱导强烈的脂肪细胞分化。这些观察结果表明，ASK1是这些侵袭性肿瘤新治疗策略的一个靶点。
