scholarly journals Topoisomerase IIβ Negatively Modulates Retinoic Acid Receptor α Function: a Novel Mechanism of Retinoic Acid Resistance

2008 ◽  
Vol 28 (6) ◽  
pp. 2066-2077 ◽  
Author(s):  
Suzan McNamara ◽  
Hongling Wang ◽  
Nessrine Hanna ◽  
Wilson H. Miller
Keyword(s):  
Retinoic Acid ◽  
Topoisomerase Ii ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Acid Resistance ◽  
Promyelocytic Leukemia ◽  
Activation Of Transcription ◽  
Retinoic Acid Receptor Α ◽  
Topoisomerase Ii Beta ◽  
Retinoic Acid Resistance

ABSTRACT Interactions between retinoic acid (RA) receptor α (RARα) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In patients with acute promyelocytic leukemia (APL), the RARα gene is fused with the promyelocytic leukemia (PML) gene via the t(15;17) translocation, resulting in the expression of a PML/RARα fusion protein. Here, we report that topoisomerase II beta (TopoIIβ) associates with and negatively modulates RARα transcriptional activity and that increased levels of and association with TopoIIβ cause resistance to RA in APL cell lines. Knockdown of TopoIIβ was able to overcome resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoIIβ in clones from an RA-sensitive cell line conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicated that TopoIIβ is bound to an RA response element and that inhibition of TopoIIβ causes hyperacetylation of histone 3 at lysine 9 and activation of transcription. Our results identify a novel mechanism of resistance in APL and provide further insight to the role of TopoIIβ in gene regulation and differentiation.

scholarly journals Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5499-5511 ◽  
Author(s):  
Kim L. Rice ◽  
Itsaso Hormaeche ◽  
Sergei Doulatov ◽  
Jared M. Flatow ◽  
David Grimwade ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Myeloid Leukemias ◽  
Direct Target ◽  
Retinoic Acid Receptor Α ◽  
Chip Chip

Abstract The t(11;17)(q23;q21) translocation is associated with a retinoic acid (RA)–insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger–retinoic acid receptor α (PLZF-RARα) and RARα-PLZF. Using a combination of chromatin immunoprecipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RARα that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RARα as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RARα promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RARα binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RARα may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RARα–transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RARα.

scholarly journals Potentiation of GATA-2 Activity through Interactions with the Promyelocytic Leukemia Protein (PML) and the t(15;17)-Generated PML-Retinoic Acid Receptor α Oncoprotein

2000 ◽  
Vol 20 (17) ◽  
pp. 6276-6286 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Masayuki Towatari ◽  
Hidehiko Saito ◽  
Tariq Enver
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Protein ◽  
Acid Receptor ◽  
Survival And Growth ◽  
Retinoic Acid Receptor Α ◽  
Zinc Finger Region

ABSTRACT The hematopoietically expressed GATA family of transcription factors function as key regulators of blood cell fate. Among these, GATA-2 is implicated in the survival and growth of multipotential progenitors. Here we report that the promyelocytic leukemia protein (PML) can complex with GATA-2 and potentiate its transactivation capacity. The binding is mediated through interaction of the zinc finger region of GATA-2 and the B-box domain of PML. The B-box region of PML is retained in the PML-RARα (retinoic acid receptor alpha) fusion protein generated by the t(15;17) translocation characteristic of acute promyelocytic leukemia (APL). Consistent with this, we provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.

scholarly journals Characterization of the Retinoid Binding Properties of the Major Fusion Products Present in Acute Promyelocytic Leukemia Cells

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1175-1185 ◽  
Author(s):  
Laura Benedetti ◽  
Arthur A. Levin ◽  
Bianca M. Scicchitano ◽  
Francesco Grignani ◽  
Gary Allenby ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Transcriptional Activation ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Binding Assays ◽  
Binding Properties ◽  
All Trans Retinoic Acid ◽  
Structural And Functional Properties ◽  
Retinoic Acid Receptor Α

Abstract The bcr1- and bcr3- promyelocytic leukemia/retinoic acid receptor α (PML/RARα) are the two major fusion proteins expressed in acute promyelocytic leukemia (APL) patients. These proteins, which are present in different lengths of PML (amino acids 1-552 and 1-394, respectively), contain most of the functional domains of PML and RARα, bind all-trans-retinoic acid (t-RA), and act as t-RA–dependent transcription factors. T-RA is an effective inducer of clinical remission only in patients carrying the t(15; 17) and expressing the PML/RARα products. However, in APL patients achieving complete remission with t-RA therapy the bcr3-PML/RARα product has been found associated with a poorer prognosis than bcr1-PML/RARα. In the present study we have investigated the structural and functional properties of the bcr3-PML/RARα in comparison to the previously characterized bcr1-PML/RARα. In particular, we have measured the binding properties of the two endogenous ligands t-RA and 9-cis-RA to both of these isoforms. T-RA binding analysis of nuclear and cytosolic extracts prepared from bcr3-PML/RARα APL patients and from bcr3-PML/RARα COS-1 transfected cells indicates that this protein is present only as high-molecular-weight nuclear complexes. Using saturation binding assays and Scatchard analyses we found that t-RA binds with slightly less affinity to the bcr3-PML/RARα receptor than to bcr1-PML/RARα or RARα (Kd = 0.4 nmol/L, 0.13 nmol/L or 0.09 nmol/L, respectively). Moreover, two different high-affinity 9-cis-RA binding sites (Kd = 0.45 and 0.075 nmol/L) were detectable in the bcr3-PML/RARα product but not in the bcr1-PML/RARα product (Kd = 0.77 nmol/L). By competition binding experiments we showed that 9-cis-RA binds with higher specificity to the bcr3-PML/RARα isoform than to the bcr1-PML/RARα or RARα. Consistent with these data, the binding of 9-cis-RA to the bcr3-PML/RARα product resulted in increased transcriptional activation of the RA-responsive element (RARE) TRE, but not of the βRARE, in transiently transfected COS-1 cells. These results provide evidence indicating that preferential retinoid binding to the different PML/RARα products can be measured.

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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