Epigenetic and RNA splicing regulation of gene expression in AML therapy resistance and relapse

Margherita Ghisi

The appearance and/or accumulation of a reservoir of Drug Tolerant Persister (DTP) cancer cells upon therapy exposure preceding and fueling the relapse of the disease, is a major obstacle to curative cancer treatments. This is a particularly relevant issue for AML, a poor prognosis form of leukemia, characterized by frequent relapses upon therapy caused by the persistence of DTP AML cells.
By making use of a combination of advanced functional genetic screening, in vivo and in vitro models of human AML and advanced molecular biology and -omics technologies, our work aims to improve our understanding of the elusive and poorly characterized drug tolerant state in AML and the mechanisms that underpin disease relapse upon therapy.
Alterations of RNA splicing and epigenetic regulation have been associated with the development, progression and therapy resistance of AML. Inspired by our previous work and the literature, our research explores the role of epigenetic and RNA splicing changes in the context of AML drug tolerance and, more in general, in the biology of this form of leukemia.
Our overarching goal is to improve our mechanistic understanding of non-genetic mechanisms sustaining leukemia progression and resistance to treatment, revealing new molecular vulnerabilities and therapeutic targets.