Modulation of the c-Maf transcription factor: a new perspective for multiple myeloma

Multiple myeloma (MM) is a malignant hematological disorder characterized by clonal proliferation of plasma cells in the bone marrow, recently proposed as a model system for the comprehension of tumor biology[1]. Over-expression of Maf basic leucine zipper (LZ) transcription factors, either by specific chromosomal translocations or by other mechanisms, occurs in 50% of MM cases[2]. c-Maf signature, in particular, is associated with a poor prognosis, high proliferation index and low median survival. The deregulation of c-Maf plays an important pathogenetic role, leading to an abnormal expression of a wide set of genes, including CCND2, ITGB7 and ARK5 and others, whose products regulate processes such as cell proliferation, adhesion, invasion and cell-cell communication[3]. In this work, Maf basic LZ has been produced by solid phase peptide synthesis (SPPS)[4] and characterized in terms of secondary structure and dimerization properties. Peptidic c-Maf dimerization inhibitors have been rationally designed and their ability to interact with synthetic LZ was studied using circular dichroism spectroscopy and MALDI TOF techniques. The putative inhibitors interacted selectively with c-Maf LZ domain, affecting the degree of structural organization and destabilizing homodimers. These molecules were able to drive the folding of c-Maf, an intrinsically disordered protein, suggesting an alternative way to interfere with transcription factors, based on a “folding distractor” rather than a “folding disruptor”. Finally, we demonstrated that the combination between protein domains SPPS and secondary and quaternary structure analysis allow to build up a simple experimental platform to test LZ dimerization inhibitors [5].