A CELL CYCLE CLOCK REGULATES THE EPIGENETIC LANDSCAPE OF AML CELLS AND DETERMINES SENSITIVITY TO LSD1 INHIBITION

Acute Myeloid Leukemia (AML) remains a complicated challenge in oncology, characterized by a complex interplay of factors that contribute to poor survival rates and resistance to chemotherapy and targeted therapies. This study presents a novel approach to unravel the layers of AML biology and treatment, focusing on the epigenetic enzyme LSD1, which is regularly found overexpressed in AML, as a therapeutic target. We revealed a crucial role for the cell cycle regulator p21 in determining sensitivity to LSD1 inhibition. Our findings further demonstrate that pharmacological prolongation of the cell cycle, specifically the G1 phase, can sensitize AML cells to LSD1 inhibitors. This is achieved through a novel combinatorial approach involving clinically approved CDK inhibitors, such as Palbociclib, with LSD1 inhibitors. Moreover, the study investigates mechanistically the implications of cell cycle manipulation, focusing on modifications of the epigenome. Our ATAC-seq investigations show that extension of the G1 phase alters chromatin accessibility. The epigenomic remodeling is further characterized by ChIP-seq and mass spectrometry experiments on genomic distribution and quantities of functionally relevant histone post-translational modifications, respectively, suggesting that those changes prime AML cells for differentiation. Intriguingly, transcriptome analyses identify the activation of transposable elements as a possible mechanism potentially driving immune responses and mediating differentiation in the treated AML cells, which we intend to further explore. The study offers the development and deciphers molecular mechanisms of a combination strategy, where use of a sub-optimal dose of a CDK inhibitor with a specific LSD1 inhibitor can be a promising treatment a for wide range of AML subtypes, and extending also to non hematopoietic tumors.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2023

Author dc:creator

• HAYATIGOLKHATMI, KOUROSH

Contributors dc:contributor

• INTERNAL ADVISOR: S. SANTAGUIDA ; EXTERNAL ADVISOR: G. ALMOUZNI ; TUTOR: S. MINUCCI ; PHD COORDINATOR: S. MINUCCI
• K. Hayatigolkhatmi
• MINUCCI, SAVERIO

• Epigenetic
• AML
• Cell Cycle
• LSD1
• Settore MED/04 - Patologia Generale

Statement dc:rights

• info:eu-repo/semantics/openAccess
• license:Creative commons
• license uri:http://creativecommons.org/licenses/by-sa/4.0/

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/hayatigolkhatmi-kourosh_phd2023-12-12
10.13130/hayatigolkhatmi-kourosh_phd2023-12-12

OAI identifier oai:identifier

oai:air.unimi.it:2434/1018352