PML nuclear bodies in the pathogenesis of acute promyelocytic leukemia: active players or innocent bystanders?

Abstract

The promyelocytic leukemia gene (PML) encodes a protein which localizes to PML-nuclear bodies (NBs), sub-nuclear multi-protein structures, which have been implicated in diverse biological functions such as apoptosis, cell proliferation and senescence. However, the exact biochemical and molecular basis of PML function up until now has not been defined. Strikingly, over a decade ago, PML-NBs were found to be disrupted in acute promyelocytic leukemia (APL) in which PML is fused to the gene encoding retinoic acid receptor alpha (RARA) due to the t(15;17) chromosomal translocation, generating the PML-RARA chimeric protein. The treatment of APL patients with all-transretinoic acid (ATRA) and arsenic trioxide which target the PML-RARA oncoprotein results in clinical remission, associated with blast cell differentiation and reformation of the PML NBs, thus linking NB integrity with disease status. This review focuses on the current theories for molecular and biochemical functions of the PML-NBs, which would imply a role in the pathogenesis of APL, whilst also discussing the intriguing possibility that their disruption may not be in itself a significant oncogenic event.

Retinoic acid signaling in cancer: The parable of acute promyelocytic leukemia

“…Mechanism of RA-Induced Cure: The Role of PML PML-RARA degradation by RA and arsenic elicits the reformation of PML nuclear bodies (NBs) in APL cells, 97-100 but the clinical significance of this observation has long remained unclear. 101 NBs are spherical structures formed in the nucleus by the aggregation of PML via coiled-coil interactions. In normal cells, the assembly of PML NBs is modulated by various stress stimuli such as DNA damage, viral infection and oxidative stress.…”

The PML-Interacting Protein DAXX: Histone Loading Gets into the Picture

“…(Grimwade and Solomon, 1997; Brown et al, 2009; de The and Chen, 2010), for detailed information on APL pathogenesis]. PML can localize to the cytoplasm [for more extensive discussion on the role of cytoplasmic PML, see (Lin et al, 2004; Giorgi et al, 2010; Pinton et al, 2011) as well as this issue of Frontiers] and the nucleus, where it forms the PML nuclear body (PML-NB), of which it is the essential component (Salomoni and Khelifi, 2006; Salomoni et al, 2008).…”

Multi-omics profiling reveals a distinctive epigenome signature for high-risk acute promyelocytic leukemia

“…In normal cells, PML regulates a wide range of proteins including transcription factors and ensures normal functioning of biological processes such as DNA damage response and microorganism resistance [ 4 ], while RARA-involved pathways are critical for terminal differentiation of myeloid cells [ 5 ]. The formation of the PML-RARA oncofusion protein disrupts normal functioning of both fusion partners expressed by wild-type alleles [ 6 ] and induces a maturation block at the promyelocytic stage [ 7 ].…”