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Effect of PML/RARA on the transcriptome of preleukemic early promyelocytes vs PML/RARA-Flt3ITD leukemic promyelocytes

ABSTRACT: Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector Two-conditions experiment: preleukemic early promyelocytes vs leukemic promyelocytes

ORGANISM(S): Mus musculus

SUBMITTER: Scott Kogan

PROVIDER: E-GEOD-59431 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.

Gaillard Coline C Tokuyasu Taku A TA Rosen Galit G Sotzen Jason J Vitaliano-Prunier Adeline A Roy Ritu R Passegué Emmanuelle E de Thé Hugues H Figueroa Maria E ME Kogan Scott C SC

Haematologica 20150618 8

Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and youn ...[more]

PMID: 26088929

Similar Datasets

Effect of PML/RARA on the transcriptome of preleukemic early promyelocytes vs PML/RARA-Flt3ITD leukemic promyelocytes

Project description:Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector

2015-07-15 | GSE59431 | GEO

Transcription profiling of human normal bone marrow CD34+ cells, promyelocytes, and neutrophils and PR9 cell line PML-RARA induction time series

Project description:To better understand the pathogenesis of acute promyelocytic leukemia (APL, FAB M3 AML), we identified genes that are expressed differently in APL cells compared to other acute myeloid leukemia subtypes, and to normal promyelocytes. Comparative gene expression analysis of 14 M3, 62 other AML (M0, M1, M2 and M4) and 5 enriched normal promyelocyte samples revealed a signature of 1,121 genes that are specifically dysregulated in M3 samples relative to other AML, and that do not simply represent normal promyelocyte expression (â??M3-specific signatureâ??). We used a novel, high throughput digital platform (Nanostring's nCounter system) to evaluate a subset of the most significantly dysregulated genes in 30 AML samples; 33 of 37 evaluable gene expression patterns were validated. In an additional analysis, we selected only genes that are dysregulated in M3 both compared to other AML subtypes, and to purified normal CD34+ cells, promyelocytes, and/or neutrophils, thereby isolating a 478 gene "composite M3 dysregulome". Surprisingly, the expression of only a few of these genes was significantly altered in PR-9 cells after PML-RARA induction, suggesting that most of these genes are not direct targets of PML-RARA. Comparison of the M3-specific signature to our previously described murine APL dysregulome revealed 33 commonly dysregulated genes, including JUN, EGR1, and TNF. Collectively, these results suggest that PML-RARA initiates a transcriptional cascade which generates a unique downstream expression signature in both primary human and mouse APL cells. Experiment Overall Design: 14 human APL/M3 AML samples were compared to 62 AML samples of other AML FAB subtypes (bone marrow aspirates collected at diagnosis, included in GSE10358), to fractionated cells from normal human bone marrow aspirates (5 CD34+ cells, 5 promyelocytes, 5 neutrophils/PMNs), and to PR9 cells before and after Zinc-induction of PML-RARA.

2008-10-26 | E-GEOD-12662 | biostudies-arrayexpress

Expression and function of PML-RARA in the multipotent hematopoietic progenitor cells of Ctsg-PML-RARA mice

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

Expression and function of PML-RARA in the multipotent hematopoietic progenitor cells of Ctsg-PML-RARA mice

2012-08-13 | E-GEOD-40022 | biostudies-arrayexpress

mCG-PML-RARA alters multipotent hematopoiesis.

2010-10-21 | GSE24728 | GEO

mCG-PML-RARA alters multipotent hematopoiesis.

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

The ability of PML/RARα to initiate leukemia is associated with markedly increased proliferation of promyelocytes despite minor changes in the transcriptome and epigenome.

Project description:Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia. DNA methylation profiling in CD34(+) early promyelocytes and CD34(-) late promyelocytes cells from PML-RARa transgenic mice vs. control mice.

2015-09-04 | E-GEOD-54038 | biostudies-arrayexpress

Normal human bone marrow CD34+ cells, promyelocytes, and neutrophils and PR9 cell line PML-RARA induction time course

Project description:To better understand the pathogenesis of acute promyelocytic leukemia (APL, FAB M3 AML), we identified genes that are expressed differently in APL cells compared to other acute myeloid leukemia subtypes, and to normal promyelocytes. Comparative gene expression analysis of 14 M3, 62 other AML (M0, M1, M2 and M4) and 5 enriched normal promyelocyte samples revealed a signature of 1,121 genes that are specifically dysregulated in M3 samples relative to other AML, and that do not simply represent normal promyelocyte expression (“M3-specific signature”). We used a novel, high throughput digital platform (Nanostring's nCounter system) to evaluate a subset of the most significantly dysregulated genes in 30 AML samples; 33 of 37 evaluable gene expression patterns were validated. In an additional analysis, we selected only genes that are dysregulated in M3 both compared to other AML subtypes, and to purified normal CD34+ cells, promyelocytes, and/or neutrophils, thereby isolating a 478 gene "composite M3 dysregulome". Surprisingly, the expression of only a few of these genes was significantly altered in PR-9 cells after PML-RARA induction, suggesting that most of these genes are not direct targets of PML-RARA. Comparison of the M3-specific signature to our previously described murine APL dysregulome revealed 33 commonly dysregulated genes, including JUN, EGR1, and TNF. Collectively, these results suggest that PML-RARA initiates a transcriptional cascade which generates a unique downstream expression signature in both primary human and mouse APL cells.

2008-09-06 | GSE12662 | GEO

Effect of PML/RARa on the transcriptome of maturing myeloid populations in vivo

Project description:Transcriptional profiling of murine cells at the GMP, Early promyelocyte (Early Pros) and Late promyelocyte (Late Pros) stages, isolated from Wt or MRP8-PML/RARa transgenics after 2 rounds of sorting. Two-conditions experiment: Wt vs PML/RARa. 3 populations: GMP, Early Pros, Late Pros. 3-4 biological replicates/population (20 samples total)

2015-06-24 | E-GEOD-54474 | biostudies-arrayexpress

Genome-wide recognition of PML/RARa binding sites

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

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