Therapy-induced PML nuclear body re-formation and p53 activation trigger acute promyelocytic leukaemia cure
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Nabila Elarouci
PROVIDER: E-GEOD-51723 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The therapy-induced PML/RARA catabolism elicits the loss of APL-initiating cell self-renewal through PML NB reformation and P53 activation. These results explain the curative activity of the RA/arsenic combination, the resistance to RA of PLZF/RARA-driven APLs and they raise the prospect that activation of this PML/P53 checkpoint might have therapeutic values in other malignancies.
2014-01-11 | GSE51723 | GEO
Project description:Acute promyelocytic leukemia (APL) is associated with PML-RARA expression and late myeloid maturation arrest. The myeloid restriction of PML-RARA dependent leukemia has been recapitulated in multiple mouse models of APL, including PML-RARA expressed from the Ctsg locus (mCG-PR). However, we report here that Ctsg expression is not limited to promyelocytes (as had previously been thought); Ctsg RNA is detectable in KLS cells, and mCG-PR mice express PML-RARA within the same compartment, an event that alters multilineage hematopoiesis. However, these animals only develop myeloid leukemia (consistent with the myeloid restriction of human PML-RARA-associated leukemia). Our results suggest that APL is shaped by myeloid- and development-specific factors that define the ultimate leukemic phenotype rather than PML-RARA acting in a committed myeloid precursor.
2010-10-21 | GSE24728 | GEO
Project description:Acute promyelocytic leukemia (APL) is associated with PML-RARA expression and late myeloid maturation arrest. The myeloid restriction of PML-RARA dependent leukemia has been recapitulated in multiple mouse models of APL, including PML-RARA expressed from the Ctsg locus (mCG-PR). However, we report here that Ctsg expression is not limited to promyelocytes (as had previously been thought); Ctsg RNA is detectable in KLS cells, and mCG-PR mice express PML-RARA within the same compartment, an event that alters multilineage hematopoiesis. However, these animals only develop myeloid leukemia (consistent with the myeloid restriction of human PML-RARA-associated leukemia). Our results suggest that APL is shaped by myeloid- and development-specific factors that define the ultimate leukemic phenotype rather than PML-RARA acting in a committed myeloid precursor. Bone marrow from individual mice expressing PML-RARA from the murine Ctg locus (mCG-PR) and littermate controls was harvested from both femurs and tibia. Standard cell lysis was performed and total RNA was extracted from the flow sorted KLS and SLAM cells. A total of 13 specimens including 3 x mCG-PR_KLS_6wks, 2 x mCG-PR_KLS_13wks,2 x mCG-PR_SLAM_7wks, 4 x WT_KLS_12-13wks (control) and 2 x WT_SLAM_6wks (control) were analyzed using Affymetrics Mouse Exon 1.0 ST platform.
2010-10-21 | E-GEOD-24728 | biostudies-arrayexpress
Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients.
2012-08-14 | GSE40022 | GEO
Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. Bone marrow from individual mice expressing PML-RARA from the murine Ctg locus (mCG-PR) and littermate controls was harvested from both femurs and tibia. Standard cell lysis was performed, and total RNA was extracted from the cells and analyzed using the Affymetrix Mouse Exon 1.0 ST platform.
2012-08-13 | E-GEOD-40022 | biostudies-arrayexpress
Project description:PML/RARa is of crucial importance in acute promyelocytic leukemia (APL) both pathologically and therapeutically. Using a genome-wide approach, we identified in vivo PML/RARa binding sites in ZnSO4 treated PR9 cells. A total of 2,979 high quality binding sites were identified, representing 1,981 unique RefSeq genes. The supplementary bed file contains all 2,979 high quality PML-RARa binding sites reported in the paper.
2009-11-26 | GSE19202 | GEO
Project description:PML-RARa contributes to the development of APL through repression of genes important in myeloid development. Through a global approach, we have identified 2,979 high quality PML-RARa binding sites in ZnSO4 induced PR9 cells. By integration the gene expression data, we found that PML/RARa target genes are transcriptionally suppressed in primary APL cells and re-activated in ATRA treated NB4 cells. This SuperSeries is composed of the SubSeries listed below.
2009-11-26 | GSE19203 | GEO
Project description:The aim of this study is to identify microRNAs (miRNAs) transcriptionnally regulated by retinoic acid (RA). For that purpose we have used the RA-based treatment of the Acute Promyelocytic Leukemia (APL) as a model. This malignancy is characterised by a differentiation arrest of granulopoiesis at the promyelocytic stage. APL is molecularly associated with reciprocal translocations that always involve the retinoic acid receptor a (RARa). In the vast majority of APL cases, a t(15;17) chromosomal translocation fuses the genes encoding the promyelocytic leukemia protein PML and RARa. The resulting PML-RARa is a transcriptional repressor that impedes the expression of RA-regulated genes notably through an aberrant recruitment of transcriptional repressors and histone deacetylases. Consequently, these genes become insensitive to physiological doses (nanoM) of all-trans-retinoic acid (ATRA) but pharmacological doses (microM), overcome the PML-RARa-mediated repression and restore normal transcription and granulocytic differentiation. The restorative effects of RA can be reproduced in vitro in the NB4 cells, which were derived from an APL patient. These cells provide an excellent model to study the transcriptional deregulations that arise in APL and the molecular effects of the anti-cancerous RA-based treatment. We also used in this study the RA-resistant cells, namely NB4-LR1 and NB4-LR2 cells. The NB4-LR1 cells do transcriptionally respond to ATRA but do not maturate. In contrast, the NB4-LR2 cells show a clear defect in RA signaling, as they harbor a truncated form of PML-RAR protein that is not sensitive to pharmacological doses of RA. First, we plan to characterize miRNAs-repressed by PML-RAR. We reasoned that if some miRNAs are repressed by this protein, then pharmacological doses of RA should abolish this repression and lead to an increase in the level of expression of the corresponding miRNAs. NB4, NB4-LR1 and NB4-LR2 cells will thus be treated for 16h with ATRA (1 microM), and miRNAs profiles will be compared. We anticipate that, the expression of a potential miRNA-repressed by PML-RAR should be up-regulated by ATRA in both NB4 and NB4-LR1 cells but remain unchanged in NB4-LR2 cells. This expression pattern should in fact be similar to those observed for known RA-regulated genes, such as RARb, a well characterized target of the RARa and PML-RAR proteins. Importantly, this experimental procedure was already validated with the identification of a miRNA repressed by PML-RAR (patent Lecellier et al. #WO 2006/048553). MiRNAs candidates obtained will then be validated by chromatin immunoprecipitation using anti-RARa and anti-PML antibodies, followed by luciferase assays in presence or absence of ATRA. Keywords: retinoic acid-mediated gene regulation To characterize miRNAs regulated by PML-RAR.
2008-11-17 | E-GEOD-11379 | biostudies-arrayexpress
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE173754 | GEO
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE173753 | GEO