Myc is essential for transformation by TEL/platelet-derived growth factor receptor beta (PDGFRbeta).
The t(5;12) translocation identified in patients with chronic myelomonocytic leukemia (CMML) encodes a TEL/platelet-derived growth factor receptor beta (PDGFRbeta) fusion protein. A key hypothesis for how the TEL/PDGFRbeta fusion protein would function as an oncogene is that it represents a constitutively active version of the normal PDGFRbeta. A link between the function of the t(5;12)-encoded TEL/PDGFRbeta fusion protein and Myc expression is suggested by the fact that Myc is induced by PDGF and is essential for entry of cells into the S phase of the cell cycle. We here show that the kinase activity of TEL/PDGFRbeta is necessary for Ba/F3 cells to acquire interleukin-3 (IL-3) independence and that, in contrast to their untransfected counterpart, Ba/F3 cells stably transfected with TEL/PDGFRbeta maintain a high level of Myc expression after removal of IL-3. Using dominant negative mutants of Myc, we show that a threshold of active Myc is essential for TEL/PDGFRbeta to transform Ba/F3 and Rat-1 cells. The findings that the kinase activity of TEL/PDGFRbeta and a threshold of active Myc are involved in TEL/PDGFRbeta transformation may allow for the development of therapeutic strategies in patients with t(5;12)+ CMML using specific inhibitors of the PDGFRbeta kinase as well as compounds designed to interfere specifically with Myc.
Bourgeade
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MF
U417 Institut de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Antoine, Paris, France.
Défachelles
A S
AS
Cayre
Y E
YE
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D016259:Genes, myc; D007377:Interleukin-3 / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D015398:Signal Transduction
C092972:CGP 53716; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor