How arsenic cures Acute Promyelocytic Leukaemia Professor Ron Hay (University of Dundee) presents his work on how arsenic cures Acute Promyelocytic Leukaemia. Hosted by Dr Joana Faria.

Seminar
This event has now finished.
  • Date and time: Friday 3 November 2023, 1pm to 2pm
  • Location: Dianna Bowles Lecture Theatre, B/K/018, Biology Building, Campus West, University of York (Map)
  • Audience: Open to alumni, staff, students (postgraduate researchers, taught postgraduates, undergraduates)
  • Admission: Free admission, booking not required

Event details

Abstract

Acute Promyelocytic Leukaemia (APL) is caused by a reciprocal chromosomal translocation t(15;17) that fuses the genes encoding Promyelocytic Leukaemia (PML) protein and retinoic acid receptor alpha (RARA). This generates the PML-RARA oncoprotein that deregulates transcriptional programmes required for the differentiation of haematopoetic progenitor cells. Thus, differentiation is blocked and promyelocytes accumulate causing leukaemia. However, most patients are now cured by a combination of arsenic trioxide (ATO) and all trans retinoic acid (ATRA). ATO induces degradation of the PML-RARA oncogene and allows the unfused version of RARA to initiate a transcriptional programme that drives the accumulated promyelocytes down a pathway of terminal differentiation that ultimately cures the disease. Treatment with ATO leads to rapid multisite modification of PML-RARA with SUMO which serves to recruit ubiquitin E3 ligases that mediate ubiquitination and ultimately proteolytic degradation by the proteasome. We have used proteomic analysis of isolated PML bodies to identify proteins recruited into PML bodies in response to arsenic treatment. Functional testing revealed a number of these components whose depletion blocked arsenic induced degradation of PML. This has allowed us to identify the cellular components involved in this process and has delineated two pathways required for arsenic induced degradation of PML-RARA that I will describe in the talk.

About the speaker

Professor Ron Hay

Ron is a Professor of Molecular Cell and Developmental Biology. He is also a Wellcome Trust Senior Investigator and a fellow of the Royal Society, the Royal Society of Edinburgh, the Academy of Medical Sciences, Academia Europaea and is a member of the European Molecular Biology Organisation. In 2012 Ron was awarded the Novartis Medal and Prize of the Biochemical Society.

Ron’s research has established conjugation with the Small Ubiquitin-like Modifier (SUMO) as an important regulatory mechanism in eukaryotes. A key role for SUMO and ubiquitin was uncovered in mediating the effects of arsenic when it is used therapeutically in the treatment of Acute Promyelocytic Leukaemia. Recently determination of the structure of a RING E3 ligase and ubiquitin-loaded E2 complex primed for catalysis has revealed the mechanism of ubiquitin modification.