From oncogene to tumor suppressor: the dual role of Myc in leukemia.

The transcription factor c-Myc strongly stimulates cell proliferation but also regulates apoptosis, senescence, cell competition and cell differentiation, and its elevated activity is a hallmark for human tumorigenesis. c-Myc induces transcription by forming heterodimers with Max and then directly binding DNA at E-box sequences. Conversely, transcription repression depends primarily on the inhibitory interaction of c-Myc/Max with Miz-1 at DNA initiator elements. We recently described a distinct mechanism of c-Myc gene regulation, in which c-Myc interacts with the retinoic acid receptor α (RARα) and is recruited to RAR DNA binding sequences (RAREs). In leukemia cells, this c-Myc/RARα complex functions either as an activator or a repressor of RARα-dependent targets through a phosphorylation switch. Unphosphorylated c-Myc interacts with RARα to repress the expression of RAR targets required for differentiation, thereby aggravating leukemia malignancy. However, if c-Myc is phosphorylated by the kinase Pak2, the c-Myc/RARα complex activates transcription of those same genes to stimulate differentiation, thus reducing tumor burden. Here, we discuss the role of c-Myc in balancing proliferation and differentiation and how modulating this previously unidentified c-Myc activity might provide alternative therapies against leukemia and possibly other types of tumors.