ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications.
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.
Chibon
Frédéric
F
INSERM U509, Molecular Pathology of Cancers, Institut Curie, Paris, France.
Mariani
Odette
O
Derré
Josette
J
Mairal
Aline
A
Coindre
Jean-Michel
JM
Guillou
Louis
L
Sastre
Xavier
X
Pédeutour
Florence
F
Aurias
Alain
A
D000008:Abdominal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D018219:Histiocytoma, Benign Fibrous / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D012186:Retroperitoneal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
D004791:Enzyme Inhibitors; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human