Myc is essential for transformation by TEL/platelet-derived growth factor receptor β (PDGFRβ)

Abstract

The t(5;12) translocation identified in patients with chronic myelomonocytic leukemia (CMML) encodes a TEL/platelet-derived growth factor receptor β (PDGFRβ) fusion protein. A key hypothesis for how the TEL/PDGFRβ fusion protein would function as an oncogene is that it represents a constitutively active version of the normal PDGFRβ. A link between the function of the t(5;12)-encoded TEL/PDGFRβ 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/PDGFRβ 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/PDGFRβ 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/PDGFRβ to transform Ba/F3 and Rat-1 cells. The findings that the kinase activity of TEL/PDGFRβ and a threshold of active Myc are involved in TEL/PDGFRβ transformation may allow for the development of therapeutic strategies in patients with t(5;12)+ CMML using specific inhibitors of the PDGFRβ kinase as well as compounds designed to interfere specifically with Myc.