This project proposes to analyze the regulatory interactions in transcription and cell proliferation of the transcription factors MYC and CTCF in hematopoietic differentiation and in aggressive lymphomas, including Diffuse Large B Cell Lymphoma (DLBCL), Double/Triple Hit Lymphoma and Burkitt lymphoma (a Burkitt form associated to Epstein-Barr infection). CTCF is a transcription factor of the zinc finger type, originally identified as MYC repressor. MYC is an oncogenic transcription factor which is deregulated in more than half of human tumors, being prevalent in lymphoma. Although MYC is activated by chromosomal translocation in some lymphoma, as in all Burkitt lymphomas and many DLBCL in most other cases MYC is transcriptionally activated through unknown mechanisms. MYC regulates transcription as a dimer with the protein MAX. Other proteins of the MAX interactome as MNT antagonize MYC transcriptional activity. Despite its importance as MYC modulator, the impact of MNT on MYC-driven lymphomagenesis has not been studied.
The project is assembled in three objectives. The first studies the expression and regulatory interactions of CTCF on MYC and BCL6, a key oncogene in aggressive lymphoma. The CTCF binding sites on BCL6 gene will be sequenced in a set of lymphomas. The second objective studies the functional interactions of CTCF and MYC in hematopoietic differentiation. We previously showed that CTCF induces erythroid differentiation in pluripotent K562 cells. Now we will investigate the mechanisms for this effect. We will also study the synthetic lethality of MYC and CDK1 in lymphoma and hematopoietic cells. In the third objective, we will analyze the interaction of MNT with REL protein and its effects in proliferation of lymphoma derived cells in the signaling of NFkB (important in aggressive lymphomas) and in the expression of CTCF and MYC. In a cohort of lymphoma patients we will study the possible correlation of the REL amplification, a frequent event in DLBCL
Entidades financiadoras y/o coordinador
- AGENCIA ESTATAL DE INVESTIGACION