Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia

Gurrieri, Carmela

doi:10.1182/blood-2003-07-2200

Cited by 67 publications

(60 citation statements)

References 23 publications

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“…Consistent with this notion is the localization of PML/RARA to cytoplasmic structures, seen in this as well as in previous studies, both in NB4 cells and in primary APL blasts. [37][38][39][40][41] Interestingly, a cytoplasmic compartment referred to as cytoplasmic assemblies of PML and nucleoporins, which appear after mitotic cell division and contain PML or PML/RARA, was found to be cleared from NB4 cells in the presence of ATRA, suggesting a possible link between the stability of these cytoplasmic structures and autophagic activity. 40 Our results showing the involvement of the mTOR pathway in the autophagy-mediated clearance of PML/RARA is supported by a recent study in which the authors demonstrated that ATRAinduced growth arrest and differentiation of acute myelogenous leukemia cells is mTOR dependent and that mTOR inhibitors further potentiates the effects of ATRA.…”

Section: Discussionmentioning

confidence: 99%

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Isakson

Bjørås

Bøe

et al. 2010

Blood

243

231

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IntroductionThe promyelocytic leukemia/retinoic acid receptor alpha (PML/ RARA) oncoprotein, which is expressed by the acute promyelocytic leukemia (APL)-specific t(15;17) chromosomal translocation, is known to inhibit granulocyte development at the promyelocytic stage of differentiation and to promote malignant transformation of hematopoietic progenitor cells mainly by acting as a repressor of gene expression. [1][2][3] All-trans retinoic acid (ATRA), the first of 2 drugs that was found to cause disease regression specifically in APL patients, interacts with the ligand binding domain present on the RARA moiety of the chimeric oncoprotein and causes both its transcriptional activation, as well as its proteolytic degradation, an effect that phenotypically leads to granulocyte differentiation of APL cells. 3,4 In later years, arsenic trioxide (ATO) also has been shown to be remarkably effective as an agent that cures APL. 4 Compared with ATRA, this drug appears to have a more limited capacity to induce differentiation and is thought to induce disease regression mainly by causing proteolytic degradation of PML/RARA. 4,5 The mechanism by which ATO causes PML/RARA proteolysis was recently shown to involve PML small ubiquitin-like modifier (SUMO)-ylation and subsequent poly-ubiquitination and proteolytic degradation of PML and PML/RARA by a protein called RNF4. 6,7 The ability of ATRA and ATO to activate disease regression through distinct molecular mechanisms that lead to PML/RARA degradation is further underscored by recent studies in which the authors showed a synergy effect of these 2 drugs both in their ability to induce clinical remission of APL patients, 8,9 as well as their capacity to cause PML/RARA degradation. 5 Thus, the ability of ATRA and ATO to activate PML/RARA degradation appears to represent a critical parameter for successful APL treatment.Two major routes for degradation of intracellular proteins exist: the ubiquitin-proteasome system (UPS) and the autophagylysosome pathway. The UPS generally is used for degradation of short-lived soluble proteins and misfolded proteins after their labeling with poly-ubiquitin chains. However, misfolded proteins that accumulate to form larger aggregates generally are poor substrates for the UPS. 10 Macro-autophagy, hereafter referred to as autophagy, involves the turnover of cytoplasmic macromolecules, protein aggregates, and defective organelles by their sequestration by double-layered membranes that form autophagosomes, which eventually fuse with lysosomes in which the sequestered contents are degraded. 11 Mice and flies lacking essential autophagy genes are characterized by increased tumorigenesis 12-14 and encompass neurodegenerative phenotypes, [15][16][17] indicating that autophagy is an important tumor-suppressive and neuroprotective mechanism.The authors of previous studies have implicated an important role of the UPS in therapy-induced degradation of PML/RARA. This role is evident from experiments showing that ATRA and ATO-induced PML/RARA degradation is b...

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Section: Discussionmentioning

confidence: 99%

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Isakson

Bjørås

Bøe

et al. 2010

Blood

243

231

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“…Thus, it could be envisioned that PML-RAR␣ constitutively triggers the oncogenic potential of c-Jun, while PML would specifically regulate c-Jun proapoptotic function modulating its UV-dependent role. As point mutations of the PML gene have been recently discovered in aggressive cases of APL, 30 it would be intriguing to test whether these mutants are defective in activating c-Jun upon DNA damage, thus further protecting APL cells from cell death induced upon DNA damage. Furthermore, this pathway could be altered in solid tumors, as cancers of various histologic origins have been found to lack expression of the PML protein.…”

Section: Discussionmentioning

confidence: 99%

The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage

Salomoni

Bernardi

Bergmann

et al. 2005

Blood

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The promyelocytic leukemia (PML) gene, a tumor suppressor inactivated in acute promyelocytic leukemia (APL), regulates apoptosis induced by DNA damage. However, the molecular mechanisms by which PML modulates apoptosis following genotoxic stress are only partially elucidated. PML is essential for p53-dependent induction of programmed cell death upon ␥-irradiation through PML-nuclear body (NB)-mediated control of p53 acetylation. Here, we show that PML selectively regulates proapoptotic transcription factors upon different types of DNA damage. We find that Pml inactivation protects fibroblasts from UV-induced apoptosis in a p53-independent manner. We demonstrate that c-Jun is required for UV

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“…14,15 Moreover, a variety of tumor suppressors have been shown to be regulated by IFN, 16,17 including ribonuclease L 6 and promyelocytic leukemia protein (PML). [18][19][20] PML is a ubiquitously expressed phosphoprotein that localizes to discrete nuclear structures called PML nuclear bodies (PML NBs). 21 Owing to alternative splicing, seven PML isoforms have been identified (PML I-VII).…”

Section: Introductionmentioning

confidence: 99%

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

et al. 2009

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The oncotropic phenotypes of several viruses correlate with tumor-associated deficiencies within interferon (IFN) signaling pathways. This observation formed the conceptual basis for developing oncolytic viruses deleted for viral proteins that inhibit the host IFN-dependent antiviral response, such as herpes simplex virus type-1 infected cell protein-0 (ICP0) and vesicular stomatitis virus matrix protein. Many viruses have evolved means to disrupt promyelocytic leukemia protein (PML) nuclear bodies. For example, ICP0 promotes PML degradation to inhibit the antiviral activities of this IFN-stimulated gene. As PML is downregulated in a variety of tumors, we hypothesized ICP0-null herpes simplex type-1 viruses are selectively oncolytic in tumors with impaired PML expression. We illustrate that ICP0-null herpes simplex type-1 viruses target tumor cells that either possess impaired PML signaling or cannot upregulate PML because of impaired IFN responsiveness. Disruption of PML signaling through overexpression of the dominant-negative protein PML-retinoic acid receptor alpha in PML-positive cells renders them sensitive to oncolysis by ICP0-null herpes simplex virus type-1 and vesicular stomatitis virus M protein mutant viruses, whereas PML overexpression reverses this phenomenon. Together, these data illustrate that PML mediates an antiviral mechanism that predicts the tropism of IFN-sensitive oncolytic viruses. To our knowledge, these viruses are the first examples of anti-cancer therapeutics capable of targeting deficiencies in PML expression.

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Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia

Cited by 67 publications

References 23 publications

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

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