MARGHERITA GHISI

TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL REGULATORS OF METABOLISM AND RESPONSE TO AML THERAPY

Dynamic mechanisms of metabolic adaptation and transcriptional plasticity play a key role in the acquisition of cancer resistance to chemotherapies. The work of our team shows that residual disease and the emergence of therapeutic resistance in leukemia cells is dependent on a change in their oxidative and mitochondrial metabolism, without the acquisition of new genetic mutations. This suggests the involvement of post-transcriptional and epigenetic regulatory mechanisms. Notably, our first data indicate that changes in RNA splicing activity are involved in the metabolic adaptation of leukemia cells, promoting resistance to treatment. RNA splicing is a modification of nascent precursor messenger RNA (mRNA) in which introns are removed and exons are joined to give rise to mature mRNA. Over 90% of human genes undergo alternative splicing to produce transcripts with different combinations of exons, increasing the diversity of the proteome. Alteration of splicing is frequently observed in cancers and a growing body of work has linked dysregulation of RNA splicing in leukemogenesis to treatment response in AML. However, our current understanding of the functional links between these changes in RNA splicing and resistance to therapy is still limited. Furthermore, while it is known that alternative splicing can affect the activity of key metabolic enzymes, little work has been done on how changes in RNA splicing can affect energy metabolism and redox status in AML.

This line of research aims to explore these questions and more generally to better understand the transcriptional and post-transcriptional mechanisms of regulation of metabolic reprogramming involved in the response to therapy of AML cells.

In summary, we aim to:

1. 1. investigate the role of RNA splicing and splicing factor mutations in the control of AML metabolism ;
   2. explore the role of RNA splicing and other transcriptional/post-transcriptional mechanisms in the metabolic reprogramming and adaptive response to therapy of resistant AML cells.