scholarly journals Aberrant Chromatin Remodeling by Retinoic Acid Receptor α Fusion Proteins Assessed at the Single-Cell Level

2007 ◽  
Vol 18 (10) ◽  
pp. 3941-3951 ◽  
Author(s):  
Jihui Qiu ◽  
Ying Huang ◽  
Guoqiang Chen ◽  
Zhu Chen ◽  
David J. Tweardy ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Fusion Proteins ◽  
Large Scale ◽  
Retinoic Acid Receptor ◽  
Chromatin Condensation ◽  
Promyelocytic Leukemia ◽  
Lac Repressor ◽  
Acid Receptor ◽  
Lac Operator

Acute promyelocytic leukemia (APL) is characterized by specific chromosomal translocations, which generate fusion proteins such as promyelocytic leukemia (PML)-retinoic acid receptor (RAR)α and promyelocytic leukemia zinc finger (PLZF)-RARα (X-RARα). In this study, we have applied lac operator array systems to study the effects of X-RARα versus wild-type RARα on large-scale chromatin structure. The targeting of these enhanced cyan fluorescent protein-lac repressor-tagged RARα-containing proteins to the gene-amplification chromosomal region by lac operator repeats led to local chromatin condensation, recruitment of nuclear receptor corepressor, and histone deacetylase complex. The addition of retinoic acid (RA) induced large-scale chromatin decondensation in cells expressing RARα; however, cells expressing X-RARα, especially PML-RARα, demonstrated insensitive response to this effect of all-trans retinoic acid (ATRA). Although we did not reveal differences in RA-dependent colocalization of either silencing mediator for retinoid and thyroid or steroid receptor coactivator (SRC)-1 with RARα versus X-RARα, the hormone-independent association between SRC-1 and X-RARα on the array has been identified. Rather, compared with cells expressing RARα, fluorescence recovery after photobleaching of live transfected cells, demonstrated decreased mobility of SRC-1 on the X-RARα–bound chromatin. Thus, the impaired ability of APL fusion proteins to activate gene transcription in response to ATRA corresponds to their reduced ability to remodel chromatin, which may link to their ability to impair the mobility of key nuclear receptor coregulators.

Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2637-2646 ◽  
Author(s):  
Shuo Dong ◽  
David J. Tweardy
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Nuclear Receptor ◽  
Fusion Proteins ◽  
Transcriptional Activity ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Maturation Arrest ◽  
Acid Receptor

Abstract Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) α is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)–unresponsive disease, STAT5b-RARα resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARα+ APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARα on the activity of myeloid transcription factors including RARα/retinoid X receptor (RXR) α, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARα bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRα and inhibited wild-type RARα/RXRα transactivation. Although STAT5b-RARα had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6–induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARα and promyelocytic leukemia zinc finger (PLZF)–RARα. SMRT was released from STAT5b-RARα/SMRT complexes by ATRA at 10−6 M, whereas TRAM-1 became associated with STAT5b-RARα at 10−7 M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARα homodimers, for the inhibition of RARα/RXRα transcriptional activity, and for stability of the STAT5b-RARα/SMRT complex. Thus, STAT5b-RARα contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRα resulting in the recruitment of SMRT and inhibition of RARα/RXRα transcriptional activity. In addition, STAT5b-RARα and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.

scholarly journals The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 882-886 ◽  
Author(s):  
RL Redner ◽  
EA Rush ◽  
S Faas ◽  
WA Rudert ◽  
SJ Corey
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Fusion Proteins ◽  
Fusion Gene ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Reading Frame ◽  
Acid Receptor ◽  
Retinoic Acid Response Element

We have studied an acute promyelocytic leukemia (APL) patient with a variant t(5;17)(q32;q12). This translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). Two alternatively spliced transcripts are expressed, which differ in 129 bases immediately upstream of the RARA sequence. The NPM sequences contained in the shorter NPM-RAR cDNA are identical to the NPM sequences contained in the NPM-ALK fusion gene expressed in t(2;5) lymphomas. The RARA sequences are the same as the RARA sequences found in the PML-RAR and PLZF-RAR fusion seen in t(15;17) and t(11;17) APL, respectively. Both NPM-RAR transcripts fuse NPM and RARA sequence in the same reading frame, to generate translation products of 57 kD and 62 kD. Both NPM-RAR proteins are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele. In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators. This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA.

scholarly journals Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

2021 ◽  
Vol 12 ◽  
pp. 204062072097698
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Yi Li ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Specific Factor ◽  
Acid Receptor ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

Detection of PML-retinoic acid receptor-α fusion transcripts in acute promyelocytic leukemia with trisomy 8 but without t(15;17)

1994 ◽  
Vol 45 (3) ◽  
pp. 212-216 ◽  
Author(s):  
Kazuma Ikeda ◽  
Kazunori Sasaki ◽  
Taizo Tasaka ◽  
Masami Nagai ◽  
Koichi Kawanishi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trisomy 8 ◽  
Acid Receptor ◽  
Fusion Transcripts ◽  
Retinoic Acid Receptor Α

scholarly journals A PML/retinoic acid receptor alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3110-3115 ◽  
Author(s):  
S Castaigne ◽  
N Balitrand ◽  
H de The ◽  
A Dejean ◽  
L Degos ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptor Alpha ◽  
Rt Pcr ◽  
Amplification Product ◽  
Chain Reaction ◽  
Acid Receptor ◽  
Polymerase Chain

Abstract The t(15;17) translocation is specifically observed in patients with promyelocytic leukemia (AML3). The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha (RAR alpha) and PML genes, resulting in PML/RAR alpha fusion transcripts. Our previous studies have shown that a polymerase chain reaction (PCR) amplification product could be obtained from the cDNA of the NB4 promyelocytic cell line from which the chimaeric PML/RAR alpha was cloned. We report here that in all 14 AML3 patients tested, reverse transcriptase-PCR (RT-PCR) allows the detection of three specific fusion products. In eight patients, one amplification product was detected corresponding to the previously described abnormal fusion. Five patients displayed a different amplified fragment corresponding to a different fusion point. One other patient always showed a third different-sized product. The different types of fusion transcripts amplified were correlated to the size of the abnormal RAR alpha transcripts detected in these patients by Northern analysis, but did not prove determinant for either the phenotypic features or the retinoic acid responsiveness in AML3 cells in this group of patients. The consistent identification by RT-PCR of the fusion of the PML and RAR alpha genes in AML3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients.

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