Highlights in Cancer Research: June 2024

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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2. Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function

Bercier, P., Wang, Q.Q., Zhang, J. et al. Cancer Discovery. 13(12), 2548-2565 (2023).
doi: 10.1158/2159-8290.CD-23-0453.

Summary of the findings

Arsenic trioxide (ATO) is a potent therapy of acute promyelocytic leukemia (APL), curing up to 70% patients as a single agent. APL is driven by the PML/RARA fusion protein, which is targeted for degradation by ATO through binding to its PML moiety. ATO modifies the nuclear distribution and stability of PML/RARA and normal PML proteins. It precipitates their self-assembly into nuclear bodies (NBs), initiating their post-translational modification by SUMO and ultimately their clearance. Yet, how ATO actually binds PML and drives NB assembly remained somehow unsettled. Arsenic efficiently binds sulfur atoms and this work has identified a critical cysteine residue in PML B2 as the key ATO target. PML B-box-2 structure reveals an alpha helix driving hydrophobic trimerization which positions these cysteines to form a trio constituting an ideal arsenic binding site. Arsenic-binding freezes this trimeric interaction, altering PML NB assembly dynamics. Impeding trimer formation (as seen with mutations observed in rare ATO-resistant APL patients) or the key cysteine residue impedes ATO-driven NB assembly, PML sumoylation and PML-RARA degradation. Overall, this study clarifies the interplay between ATO and PML, which underlies APL cure.

PML B2 self-assembles as a homo-trimer which contributes to PML nuclear body (NB) formation. Arsenic trioxide (ATO) binds to 3 critical cysteine residues positioned by the trimer, freezing NB dynamics and enforcing NB formation. This triggers sumoylation/ degradation of PML-RARA, driving acute promyelocytic leukemia (APL) cure.

Future impact

PML modulates response to multiple stress in vivo, including oxidative stress. The cysteine trio identified here represents the PML redox sensing center, highjacked by ATO during APL therapy. PML is required for efficient therapy response to other drugs that ATO. Exploring PML mutants defective for oxidative stress sensing could shed a new light on the role of therapy-driven oxidative stress in drug response.