Myc is essential for transformation by TEL/platelet-derived growth factor receptor beta (PDGFRbeta).

Abstract

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.

• Authors: M F Bourgeade, A S Défachelles, Y E Cayre
• Journal: Blood (Blood) Vol. 91 Issue 9 Pg. 3333-9 (May 01 1998) ISSN: 0006-4971 [Print] United States
• PMID: 9558390 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CGP 53716
• Enzyme Inhibitors
• Interleukin-3
• Proto-Oncogene Proteins c-myc
• Pyridines
• Pyrimidines
• Receptor Protein-Tyrosine Kinases
• Receptors, Platelet-Derived Growth Factor

Topics

• Animals
• Cell Division
• Cell Transformation, Neoplastic
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic
• Genes, Dominant
• Genes, myc
• Interleukin-3 (physiology)
• Proto-Oncogene Proteins c-myc (physiology)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
• Receptors, Platelet-Derived Growth Factor (physiology)
• Signal Transduction