Luciano Nicosia

First name
Luciano
Last name
Nicosia
Academic Year
Year of Study
Thesis Title
Chromatin Proteomics dissects the mechanism of action of LSD1 inhibitors in Acute Promyelocytic Leukemia
Thesis Abstract



Lysine specific-demethylase 1 (LSD1) is aberrantly expressed in acute myeloid leukemia (AML) and is emerging as a promising target for the epigenetic therapy of different AML subtypes. The Experimental Therapeutic Unit at the IFOM-IEO Campus optimized potent and specific LSD1 inhibitors, already characterized in vitro for their selectivity and in vivo for their anti-proliferative effects on self-renewing AML cells. In my thesis project, I studied the effects of these compounds on the pattern of histone post-translational modifications (PTMs) and on the LSD1 interaction network in NB4-APL cells (an AML subtype), using a panel of quantitative mass-spectrometry strategies. We discovered that a 24-hour treatment with the inhibitors alters the levels of histone modifications (increases H3K4me2, H3K27me2 and H3K27me3, and decreases H3K27me1). LSD1 knock-out NB4 cells display similar changes in histone PTMs, strongly suggesting a specific association with the cellular response to LSD1 inhibition. We also identified the complete set of LSD1 interactors in our model using SILAC-based proteomics, most of which are involved in chromatin remodelling and transcription regulation activities. The analysis of the LSD1-interactome after drug treatment identified two LSD1 interactors (GFI1 and GSE1) with decreased binding. Inhibition of the LSD1- GFI1 interaction promoted reduction of cell proliferation and differentiation of NB4 cells. Regarding the LSD1-GSE1 interaction, we found that GSE1 down-regulation and LSD1 inhibition up-regulated a common set of genes involved in “cytokine-mediated signalling” and “regulation of apoptosis”, thus suggesting the existence of a regulatory LSD1-GSE1 axis controlling the transcription of these genes. Collectively, these data provide novel insights into the molecular activity of LSD1 and its inhibitors in APL cells.



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