REVTRANSLOC: Reversing the effect of t(9;11) translocation in Acute Myeloid Leukemia (AML)

 

The main objective of the project REVTRANSLOC is to reverse the effects of a translocation on the expression of the resulting fusion protein. To achieve this, the researchers rely on the hypothesis that the three-dimensional organisation of the genome plays a role in how chromosomal translocations contribute to gene activation through the so-called "enhancer hijacking" mechanism.

 

This proposal builds on two recent studies from the Structural Genomics Group at CNAG. First, the development of an unbiased method to integrate epigenetic and genome structure data. Second, the generation of a novel mouse cell line carrying the t(4;9) translocation with conditional expression of the Mll-Af9 fusion protein.  

 

The Group will fully characterise this new cell line during early hematopoietic differentiation, focusing on the epigenetics surrounding the translocation breakpoint (Objective 1). Once this is achieved, we will design, based on genome structure, what we call a "Structure-Based Genome Editing" approach— a series of CRISPR-based experiments to alter the expression of the Mll-Af9 fusion gene (Objective 2). Finally, we will perform epigenetic and functional characterization of the mutant cell lines (Objective 3).  

 

The expected outcome of this proposal is the characterisation of the regulatory landscape of the Mll-Af9 fusion gene, providing direct insights into how its expression can be modulated. If successful, our findings could lay the groundwork for further characterisation of the initiation and progression of Acute Myeloid Leukemia (AML) in patients carrying this fusion gene.

 

The project PID2023-151484NB-I00 is funded by the Ministerio de Ciencia, Innovación y Universidades of Spain (MICIU/AEI/10.13039/501100011033/ FEDER/UE).