I2PP2A (SET) and Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) as novel therapeutic targets forMixed Lineage Leukaemia(MLL)

Abstract

Mixed Lineage Leukaemia (MLL) is an aggressive form of blood cancer which predominantly affects children as results of rearrangements of the MLL (KMT2A) gene at 11q23. MLL accounts for more than 70% of infant Acute Lymphoblastic Leukaemia (ALL) and between 35-50% of infant Acute Myeloid Leukaemia (AML) and, presents a very poor survival. Indeed, only 40% of the MLL patients approaches 5-years survival rate. Although new treatments have been devised to target the activity of KMT2A fusion proteins, none of these have been translated into new therapies for patients and MLL is a leukaemia of unmet clinical need.
Several recent papers have identified protein kinases as hyperactivated in MLL leukaemia and potential target for treatment. Our group is investigating the contribution of Protein Phosphatase 2A (PP2A), one of the upstream regulators of protein kinases, in MLL. Our results showed that the downstream targets of this phosphatase were constitutively deregulated and hyperactivated in MLL, suggesting a potential inactivation of PP2A in this disease. SET and CIP2A are the best well-known endogenous inhibitors of PP2A. SET directly interacts with the catalytic subunit of PP2A and impairs its activity towards the phosphorylation of AKT, ERK and GSK3-ß, whereas CIP2A modulates the activity of the phosphatase by direct interaction with the structural and regulatory subunit PP2A/B56 and by preventing the dephosphorylation of a PP2A downstream target and potent oncoprotein known as c-Myc. Published studies showed that therapeutic targeting of SET and CIP2A, rescued PP2A activity and blocked malignant proliferation in solid tumours and haematological malignancies. In this study I investigated for the first time the molecular profile of SET and CIP2A in MLL. Importantly, my findings showed that SET and CIP2A are essential proteins involved in MLL self renewal of MLL and that their pharmacological inhibition blocks MLL proliferation. The impact of these data open new avenues of research into promising and treatments for this disease, with the aim of sparing the MLL patients from toxic chemotherapy treatment and improving their survival chances.

Date of Award	23 Mar 2022
Original language	English
Awarding Institution	University of Roehampton
Sponsors	University of Roehampton Vice-Chancellor’s Scholarship
Supervisor	Yolanda Calle (Director of Studies), Maria Esposito (Co-Supervisor) & Bela Wrench (Co-Supervisor)