Centro Nacional de Biotecnología CSIC (CNB)

Cancer is a devastating disease that causes about 8 million deaths each year worldwide (1.7 million in Europe). Since early 70s, many genes have been discovered as major drivers of tumor progression. Among them, myc protooncogenes (n, l and c-myc) have been shown as prominent factors in the development of a diverse and numerous group of human cancers.  As proof, it is estimated that about 50% of all human cancers show constitutively enhanced expression of at least one of the members of the Myc family.  The Myc proteins (N-, L- and c-Myc)  are transcription factors that contain a basic region/helix-loop-helix/leucine zipper (bHLHZip) domain that mediates DNA binding and heterodimerization with its mandatory partner Max. Deregulation of myc protoongenes can occur by mechanisms directly affecting either one of the myc genes such as amplification, or by altering the signalling pathways controlling their expression. Myc/Max functions encompases a wide spectrum of biological processes due to the variety of target genes that are regulated by these proteins.  Among these, cell proliferation, differentiation and apoptosis are likely the most studied. It is generally assumed by the majority of scientific reports that in order to to activate or repress target genes Myc proteins must heterodimeraze with Max and bind to specific regulatory regions.  However, no definitive data have addressed specifically the role of Myc/Max interplay in vivo. Data generated by our group showed that Myc/Max functional collaboration in B lymphocytes is more complex than initially anticipated. In fact, Myc/Max seem to be dispensable for B lymphocyte differentiation for which they were originally thought to be required. In this proposal, we will analyze the functional relationship between Myc and Max in physiological and pathological scenarios in vivo such as B lymphocyte proliferation/replication and Myc-induced B lymphomas, respectively.  For this, we have generated new and complex genetically modified mouse models that specifically allow to address these questions. Based on our preliminary results, we aim to characterize a new role of Myc/Max during DNA replication in B lymphocytes.  In addition, we will define the role/s of Myc/Max in the generation and/or the maintenance of B lymphomas and identify Max-independent Myc targets as potential therapeutic tools. Due to the central role of Max, we expect that our results will have a relevant impact on the current knowledge of Myc physiology and pathology. 

Biomolecules & Cell D.
Molecular Biomedicine
Ignacio Moreno de Alborán