PML tumour suppression and beyond: Therapeutic implications

Abstract

a b s t r a c tRecognition of the tumour suppressive capacity of the Promyelocytic Leukemia protein (PML) has emerged beyond its identification through APL, to a broad spectrum of tumors. This ability has chiefly been linked to its role as a core component of dynamic structures termed PML Nuclear Bodies (PML-NBs). In response to a variety of stresses, key factors and their molecular modifiers are recruited to PML-NBs, where activating modifications are facilitated, leading to a cellular stress response. PML was also found to perform anti-tumourigenic functions through cytoplasmic activities. Surprisingly, important recent research defined growth promoting capabilities of PML, which significantly challenges the notion of a 'classic' tumour suppressor. Through metabolic reprogramming, PML can afford a selective advantage for tumor cells in certain settings. The multiple forms in which PML exists are the likely explanation of this functional diversity. This behavioral ambiguity however raises a significant challenge to the design of strategies to therapeutically target PML. In this review we discuss this change of paradigm in the PML field and its ramifications, particularly for tailoring cancer therapies.

TRIM proteins in blood cancers

“…Overall, these studies are in agreement with PML’s widely reported function as a tumour suppressor in a variety of both haematopoietic and solid tumours (Gamell et al 2014 ), however, chronic myeloid leukaemia (CML) is an exception to this. CML is a myeloproliferative disorder that, in common with APL, is characterised by a specific chromosomal translocation, in this case t(9;22), which gives rise to the tyrosine kinase BCR-ABL.…”

Multimodal Light Microscopy Approaches to Reveal Structural and Functional Properties of Promyelocytic Leukemia Nuclear Bodies

“…Functional assays in mice expressing PML but lacking PML NBs showed impaired homologous recombination (HR) and non-homologous end-joining repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage ( 89 ). Thus, although the physiological function of PML and the nuclear bodies have not been thoroughly elucidated, their tumor-suppressive role by supporting DNA damage response pathways may be common to all of these potential functions ( 19 , 89 ).…”

“…A better understanding of the biophysical and biochemical mechanisms by which PML and/or the PML nuclear bodies participate in genome maintenance is expected to facilitate the development of therapeutic strategies for the treatment of PML-related diseases ( 19 ).…”

Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

“…Promyelocytic leukemia protein (PML), also named TRIM19, belongs to the tripartite motif family (TRIM) of proteins that contain a RING finger, two B-boxes, and an α-helical coiled-coil (RBCC) domain [ 9 , 10 ]. As a major component of PML nuclear bodies (NBs) (also known as nuclear domain 10) [ 11 ], PML is involved in diverse cellular processes, including proliferation, apoptosis, gene transcription, and DNA damage response [ 12 – 14 ]. PML expression is increased by IFNs [ 15 , 16 ].…”