[Frontiers in Bioscience 14, 1684-1707, January 1, 2009]

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

Nicola J.M. Brown, Michal Ramalho, Eva W. Pedersen, Eva Moravcsik, Ellen Solomon, David Grimwade

Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. The PML gene 2.2. PML nuclear bodies (PML-NBs)
3. PML-NB disruption and acute promyelocytic leukemia (APL) 3.1. t (15;17) associated APL and PML-NB disruption
3.2. Alternative APL Fusions
3.3. Homodimerization of the APL fusion proteins
3.4. Is forced dimerization of RARA and transcriptional repression sufficient for leukemogenesis?
4. Evidence supporting PML-NB disruption as an "active player" in leukemogenesis
4.1. PML-NBs, tumor suppression and cancer
4.2. Further evidence supporting a role for the PML protein in the pathogenesis of APL
4.3. How does PML-NB disruption affect their constituent proteins and what are the possible downstream consequences?
4.3.1. Myeloid differentiation
4.3.2. RNA processing and translation
4.3.3. Intracellular proteolysis
4.3.4. Post-translational modifications of proteins
4.3.5. Apoptosis
4.3.6. Genome stability
4.3.7. Gene transcription
5. PML-NB disruption may be an "innocent bystander" effect in APL
5.1. Lack of PML-NB disruption in the alternative APL fusions
5.2. PML-NB formation is not required for PML induced premature senescence
5.3. Lack of a major impact of PML-NB disruption on gene expression profiles
5.4. The role of cytoplasmic PML
5.5. PML-NB functions: "guilt by association"
5.6. Apoptosis
6. Perspective: Is PML-NB disruption an "active player" or" innocent bystander" in the pathogenesis of APL?
7. Acknowledgements
8. References

1. 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.