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.

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 PIC-1/SUMO-1-Modified PML-Retinoic Acid Receptor α Mediates Arsenic Trioxide-Induced Apoptosis in Acute Promyelocytic Leukemia

1999 ◽  
Vol 19 (7) ◽  
pp. 5170-5178 ◽  
Author(s):  
Thomas Sternsdorf ◽  
Elena Puccetti ◽  
Kirsten Jensen ◽  
Dieter Hoelzer ◽  
Hans Will ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Acid Receptor ◽  
Retinoic Acid Receptor Α ◽  
Induced Apoptosis

ABSTRACT Fusion proteins involving the retinoic acid receptor α (RARα) and PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemia (APL). APLs with PML-RARα or PLZF-RARα fusion protein differ only in their response to retinoic acid (RA) treatment: the t(15;17) (PML-RARα-positive) APL blasts are sensitive to RA in vitro, and patients enter disease remission after RA treatment, while those with t(11;17) (PLZF-RARα-positive) APLs do not. Recently it has been shown that complete remission can be achieved upon treatment with arsenic trioxide (As2O3) in PML-RARα-positive APL, even when the patient has relapsed and the disease is RA resistant. This appears to be due to apoptosis induced by As2O3 in the APL blasts by poorly defined mechanisms. Here we report that (i) As2O3induces apoptosis only in cells expressing the PML-RARα, not the PLZF-RARα, fusion protein; (ii) PML-RARα is partially modified by covalent linkage with a PIC-1/SUMO-1-like protein prior to As2O3 treatment, whereas PLZF-RARα is not; (iii) As2O3 treatment induces a change in the modification pattern of PML-RARα toward highly modified forms; (iv) redistribution of PML nuclear bodies (PML-NBs) upon As2O3 treatment is accompanied by recruitment of PIC-1/SUMO-1 into PML-NBs, probably due to hypermodification of both PML and PML-RARα; (v) As2O3-induced apoptosis is independent of the DNA binding activity located in the RARα portion of the PML-RARα fusion protein; and (vi) the apoptotic process is bcl-2 and caspase 3 independent and is blocked only partially by a global caspase inhibitor. Taken together, these data provide novel insights into the mechanisms involved in As2O3-induced apoptosis in APL and predict that treatment of t(11;17) (PLZF-RARα-positive) APLs with As2O3 will not be successful.

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.

Pharicin B, a Novel Diterpenoid, Stabilizes Retinoic Acid Receptor-α Protein and Induces Differentiation of AML Cells in the Presence of Physiological Doses of ATRA.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1601-1601
Author(s):  
Guo-Qiang Chen ◽  
Zhi-Min Gu ◽  
Mei-Yi Zhou ◽  
Ying-Li Wu ◽  
Ying Huang
Keyword(s):  
Retinoic Acid ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Chinese Herb ◽  
Promyelocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Dietary Vitamin ◽  
Acid Receptor ◽  
Retinoic Acid Receptor Α

Abstract Retinoids, a generic term that covers compounds including both naturally dietary vitamin A (retinol) metabolites and active synthetic analogs, exert their pleiotropic effects such as anticancer activity through the three retinoic acid receptors (RARs) subtypes [RARα, RARβ and RARγ]. The most impressive example of retinoid anticancer activity is the successful application of all-trans retinoic acid (ATRA) in the treatment of patients with acute promyelocytic leukemia (APL), a unique subtype of acute myelogenous leukemia (AML) which characterized with the specific reciprocal chromosome translocation t(15;17) that results in the expression of leukemia-promoting promyelocytic leukemia-retinoic acid receptor-α (PML-RARα) chimeric protein. However, retinoid resistance frequently occurred in ATRA-treated patients. Isodon xerophilus, a perennial shrub native to Southern China, has been used as an anti-tumor, anti-inflammatory, and anti-microbial agent in Chinese herb medicine for a long history. During the past 30 years, a large number of ent-kauranoids have been isolated from the genus Isodon, many of which exhibit potent antitumor activities with a relatively low toxicity. In this work, we identified a novel ent-kaurene diterpenoid named pharicin B to rapidly stabilize RARα as well as PML-RARα protein in AML cell lines. More intriguingly, it also antagonizes ATRA-induced degradation of RARα and PML-RARα proteins. The interesting finding promotes us to investigate its possible effects on AML cells. Our results demonstrated that pharicin B at nontoxic concentration suppresses growth in APL cell line NB4 and myeloblactic leukemic U937 and THP-1 cell lines. Together with exceedingly low concentration of ATRA and RARα specific agonist AM580 existed, pharicin B significantly triggered all the three cell lines and some NB4-derived ATRA-resistant cell lines such as NB4-MR2 and NB4-LR1 (but not NB4-LR2) to undergo myeloid maturation, as evidenced by morphology, CD11/CD14 expression and NBT reduction test. All these results proposed that pharicin B would be a good tool for investigating mechanisms of RARα stabilization and degradation induced by ATRA as well as retinoid resistance, and its combination with ATRA might present the clinical potentials for differentiation-inducing therapy of APL and other AML patients.

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