The promyelocytic leukemia nuclear body: sites of activity?

2002 ◽  
Vol 80 (3) ◽  
pp. 301-310 ◽  
Author(s):  
Christopher H Eskiw ◽  
David P Bazett-Jones
Keyword(s):  
Retinoic Acid Receptor ◽  
Eukaryotic Cell ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Leukemic Cells ◽  
Pml Bodies ◽  
Nuclear Events ◽  
Cellular Stresses

The promyelocytic leukemia (PML) nuclear body is one of many subnuclear domains in the eukaryotic cell nucleus. It has received much attention in the past few years because it accumulates the promyelocytic leukemia protein called PML. This protein is implicated in many nuclear events and is found as a fusion with the retinoic acid receptor RARα in leukemic cells. The importance of PML bodies in cell differentiation and growth is implicated in acute promyelocitic leukemia cells, which do not contain PML bodies. Treatment of patients with drugs that reverse the disease phenotype also causes PML bodies to reform. In this review, we discuss the structure, composition, and dynamics that may provide insights into the function of PML bodies. We also discuss the repsonse of PML bodies to cellular stresses, such as virus infection and heat shock. We interpret the changes that occur as evidence for a role of these structures in gene transcription. We also examine the role of the posttranslational modification, SUMO-1 addition, in directing proteins to this nuclear body. Characterization of the mobility of PML body associated proteins further supports a role in specific nuclear events, rather than the bodies resulting from random accumulations of proteins.Key words: promyelocytic leukemia, nucleus, transcription, nuclear bodies.

scholarly journals Arsenic-Induced SUMO-Dependent Recruitment of RNF4 into PML Nuclear Bodies

2010 ◽  
Vol 21 (23) ◽  
pp. 4227-4239 ◽  
Author(s):  
Marie-Claude Geoffroy ◽  
Ellis G. Jaffray ◽  
Katherine J. Walker ◽  
Ronald T. Hay
Keyword(s):  
Retinoic Acid Receptor ◽  
E3 Ligase ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dependent Manner ◽  
Nuclear Trafficking ◽  
Sumo Modification ◽  
Ubiquitin E3 Ligase ◽  
Pml Nuclear Bodies

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.

scholarly journals Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation

2001 ◽  
Vol 193 (12) ◽  
pp. 1361-1372 ◽  
Author(s):  
Valérie Lallemand-Breitenbach ◽  
Jun Zhu ◽  
Francine Puvion ◽  
Marcel Koken ◽  
Nicole Honoré ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Matrix ◽  
Viral Infections ◽  
Retinoic Acid Receptor ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Acid Receptor ◽  
Pml Nuclear Bodies ◽  
Retinoic Acid Receptor Α

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.

Role of SUMO-1–modified PML in nuclear body formation

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2748-2752 ◽  
Author(s):  
Sue Zhong ◽  
Stefan Müller ◽  
Simona Ronchetti ◽  
Paul S. Freemont ◽  
Anne Dejean ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Critical Role ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Localization Pattern ◽  
Body Formation ◽  
Functional Relevance ◽  
Do So

The tumor-suppressive promyelocytic leukemia (PML) protein of acute promyelocytic leukemia (APL) has served as one of the defining components of a class of distinctive nuclear bodies (NBs). PML is delocalized from NBs in APL cells and is degraded in cells infected by several viruses. In these cells, NBs are disrupted, leading to the aberrant localization of NB proteins. These results have suggested a critical role for the NB in immune response and tumor suppression and raised the question of whether PML is crucial for the formation or stability of NB. In addition, PML is, among other proteins, covalently modified by SUMO-1. However, the functional relevance of this modification is unclear. Here, we show in primary PML−/− cells of various histologic origins, that in the absence of PML, several NB proteins such as Sp100, CBP, ISG20, Daxx, and SUMO-1 fail to accumulate in the NB and acquire aberrant localization patterns. Transfection of PML in PML−/−cells causes the relocalization of NB proteins. By contrast, a PML mutant that can no longer be modified by SUMO-1 fails to do so and displays an aberrant nuclear localization pattern. Therefore, PML is required for the proper formation of the NB. Conjugation to SUMO-1 is a prerequisite for PML to exert this function. These data shed new light on both the mechanisms underlying the formation of the NBs and the pathogenesis of APL.

scholarly journals FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1495-1506 ◽  
Author(s):  
Cécile Esnault ◽  
Ramy Rahmé ◽  
Kim L. Rice ◽  
Caroline Berthier ◽  
Coline Gaillard ◽  
...  
Keyword(s):  
Risk Factor ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
P53 Signaling ◽  
Pml Nuclear Bodies ◽  
All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3-internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for this effect remain unknown. Using mouse APL models, we unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response. Remarkably, although the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is blunted, as is PML nuclear body reformation and activation of P53 signaling. Critically, the combination of ATRA and arsenic fully rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL eradication. Moreover, arsenic targeting of normal PML also contributes to APL response in vivo. These unexpected results explain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination.

scholarly journals The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body

2001 ◽  
Vol 152 (5) ◽  
pp. 1099-1106 ◽  
Author(s):  
François-Michel Boisvert ◽  
Michael J. Kruhlak ◽  
Alan K. Box ◽  
Michael J. Hendzel ◽  
David P. Bazett-Jones
Keyword(s):  
State Level ◽  
Camp Response Element Binding ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dynamic Component ◽  
Pml Nuclear Bodies ◽  
Pml Bodies ◽  
Element Binding Protein ◽  
Transcription Coactivator

The transcription coactivator and histone acetyltransferase CAMP response element–binding protein (CBP) has been demonstrated to accumulate in promyelocytic leukemia (PML) bodies. We show that this accumulation is cell type specific. In cells where CBP does not normally accumulate in PML bodies, it can be induced to accumulate in PML bodies through overexpression of either CBP or Pml, but not Sp100. Using fluorescence recovery after photobleaching, we demonstrate that CBP moves rapidly into and out of PML bodies. In contrast, Pml and Sp100 are relatively immobile in the nucleoplasm and within PML nuclear bodies. They possess the characteristics expected of proteins that would play a structural role in the integrity of these subnuclear domains. Our results are consistent with CBP being a dynamic component of PML bodies and that the steady-state level in these structures can be modulated by Pml.

scholarly journals Nuclear body phase separation drives telomere clustering in ALT cancer cells

2020 ◽  
Vol 31 (18) ◽  
pp. 2048-2056 ◽  
Author(s):  
Huaiying Zhang ◽  
Rongwei Zhao ◽  
Jason Tones ◽  
Michel Liu ◽  
Robert L. Dilley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Separation ◽  
Cancer Cells ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Induce Phase Separation ◽  
Induce Phase

A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

scholarly journals Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination

2018 ◽  
Vol 46 (1) ◽  
pp. 418-430 ◽  
Author(s):  
Deneshia J. McIntosh ◽  
Treniqka S. Walters ◽  
Ifeanyi J. Arinze ◽  
Jamaine Davis
Keyword(s):  
Gene Transcription ◽  
Ring Finger ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Heme Oxygenase 1 ◽  
Ring Finger Protein ◽  
Whole Cell ◽  
Cell Lysates ◽  
Finger Protein

Background/Aims: The transcription factor Nrf2 is a master regulator of the antioxidant defense system, protecting cells from oxidative damage. We previously reported that the SUMO-targeted E3 ubiquitin ligase (STUbL), RING finger protein 4 (RNF4) accelerated the degradation rate of Nrf2 in promyelocytic leukemia-nuclear body (PML-NB)-enriched fractions and decreased Nrf2-mediated gene transcription. The mechanisms that regulate Nrf2 nuclear levels are poorly understood. In this study, we aim to explore the role of the second mammalian STUbL, Arkadia/RNF111 on Nrf2. Methods: Arkadia mediated ubiquitination was detected using co-immunoprecipitation assays in which whole cell lysates were immunoprecipated with anti-Nrf2 antibody and Western blotted with anti-hemagglutinin (HA) antibody or anti-Lys-48 ubiquitin-specific antibody. The half-life of Nrf2 was detected in whole cell lysates and promyelocytic leukemia-nuclear body enriched fractions by cycloheximide-chase. Reporter gene assays were performed using the antioxidant response element (ARE)-containing promoter Heme oxygenase-1 (HO-1). Results: We show that Arkadia/RNF111 is able to ubiquitinate Nrf2 resulting in the stabilization of Nrf2. This stabilization was mediated through Lys-48 ubiquitin chains, contrary to traditionally degradative role of Lys-48 ubiquitination, suggesting that Lys-48 ubiquitination of Nrf2 protects Nrf2 from degradation thereby allowing Nrf2-dependent gene transcription. Conclusion: Collectively, these findings highlight a novel mechanism to positively regulate nuclear Nrf2 levels in response to oxidative stress through Arkadia-mediated K48-linked ubiquitination of Nrf2.

AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1520-1531 ◽  
Author(s):  
M Gianni ◽  
M Li Calzi ◽  
M Terao ◽  
G Guiso ◽  
S Caccia ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Stable Phase ◽  
Differentiation Markers

All-trans retinoic acid (ATRA) is successfully used in the cyto- differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia- specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells.

Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto

2001 ◽  
Vol 19 (20) ◽  
pp. 4023-4028 ◽  
Author(s):  
Giorgina Specchia ◽  
Francesco Lo Coco ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Paola Fazi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Increased Risk ◽  
Junction Type ◽  
Wbc Count

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

scholarly journals In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

2006 ◽  
Vol 203 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Hiromichi Matsushita ◽  
Pier Paolo Scaglioni ◽  
Mantu Bhaumik ◽  
Eduardo M. Rego ◽  
Lu Fan Cai ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylases ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative

The promyelocytic leukemia–retinoic acid receptor α (PML-RARα) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARα to inhibit RARα function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1–RARα fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RARα mutants, as well as that of PML-RARα mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARα did act as a bona fide DN RARα mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARα mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML−/− and p53−/− compound mutants lends support to a model by which the RARα and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

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