Finding a role for PML in APL pathogenesis: a critical assessment of potential PML activities

Abstract

In normal mammalian cells the promyelocytic leukemia protein (PML) is primarily localized in multiprotein nuclear complexes called PML nuclear bodies. However, both PML and PML nuclear bodies are disrupted in acute promyelocytic leukemia (APL). The treatment of APL patients with all-trans retinoic acid (ATRA) results in clinical remission associated with blast cell differentiation and reformation of the PML nuclear bodies. These observations imply that the structural integrity of the PML nuclear body is critically important for normal cellular functions. Indeed, PML protein is a negative growth regulator capable of causing growth arrest in the G 1 phase of the cell cycle, transformation suppression, senescence and apoptosis. These PML-mediated, physiological effects can be readily demonstrated. However, a discrete biochemical and molecular model of PML function has yet to be defined. Upon first assessment of the current PML literature there appears to be a seemingly endless list of potential PML partner proteins implicating PML in a variety of regulatory mechanisms at every level of gene expression. The purpose of this review is to simplify this confusing field of research by using strict criteria to deduce which models of PML body function are well supported.

PML4 induces differentiation by Myc destabilization

“…Moreover, different PML isoforms might act in parallel on Myc in different pathways and/or promoters. Analyzing the exact expression profile of PML isoforms in different cell types might provide important clues on how PML can contribute to the large number of different and in part tissue-specific functions that were reported (Salomoni and Pandolfi, 2002;Strudwick and Borden, 2002).…”

“…The PML protein is the scaffolding component of subnuclear compartments called PML nuclear bodies (NBs, also designated PML oncogenic domain or nuclear domain 10). PML NBs have been shown to play a role in a still increasing number of cellular functions including growth suppression, genomic stability, apoptosis, DNA repair, as well as transcriptional response to interferon (Salomoni and Pandolfi, 2002;Strudwick and Borden, 2002). Taking these functions into account, it is not surprising that PML has a tumor suppressive role, and its alteration is implicated in cancer pathogenesis, including leukemia (Salomoni and Pandolfi, 2002).…”

The promyelocytic leukemia protein stimulates SUMO conjugation in yeast

“…Several PML splicing isoforms are expressed in mammalian cells, all of which contain a RING-finger domain, two RING-like motifs (B1 and B2 boxes) and a coiled coil domain (Jensen et al, 2001). The PML:RARa fusion protein causes a block in myeloid progenitor cell differentiation that is relieved by alltrans-retinoic acid (ATRA) (Strudwick and Borden, 2002). ATRA-induced differentiation of APL blasts is accompanied by PML:RARa destruction, and by redistribution of wild-type PML from aberrant nuclear structures to PML-NBs (Weis et al, 1994).…”

N4BP1 is a newly identified nucleolar protein that undergoes SUMO-regulated polyubiquitylation and proteasomal turnover at promyelocytic leukemia nuclear bodies

“…Another much-studied nuclear compartment is the promyelocytic leukemia (PML) nuclear body (NB), also known as the PML oncogenic domain (POD) or nuclear domain 10 (ND10). Although its function is still not completely understood, proteins crucial for apoptosis, transcription and cell-cycle regulation, among other cellular functions, localize to PML NBs, and a number of human diseases are associated with their loss or alteration (Rego et al, 2001;Strudwick and Borden, 2002;Bernardi and Pandolfi, 2007;Bernardi et al, 2008;Borden, 2008;Torok et al, 2009).…”