PML-RARa induces dynamic changes in genome architecture during leukemic transformation
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ABSTRACT:
PROVIDER: PRJNA637385 | ENA |
REPOSITORIES: ENA
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Project description:Acute Promyelocytic Leukemia (APL) is a fatal subtype of leukemia driven by the translocation between genes encoding the Promyelocytic Leukemia (PML) protein and the Retinoic Acid Receptor alpha (RARa) protein. We use mouse hematopoietic progenitor cells expressing PML-RARa and dissect the dynamic changes in the epigenome, transcriptome and genome architecture triggered by the expression of this oncogenic transcription factor during leukemic transformation. We find that PML-RARa induces a continuum of topologic and transcriptional alterations, mostly affecting distal regulatory elements. Furthermore, we identify Klf4 ― a master regulator of hematopoietic differentiation ― as an early mis-regulated gene during leukemogenesis, and deconstruct the dynamic alterations in long-range interactions, histone modifications and transcriptional output triggered by PML-RARa expression at the Klf4 locus. Our study provides a comprehensive overview of the dynamic genomic and transcriptomic alterations induced by PML-RARa, which ultimately block hematopoietic differentiation and induce leukemic transformation.
2022-06-09 | GSE151837 | GEO
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 Two-conditions experiment: preleukemic early promyelocytes vs leukemic promyelocytes
2015-07-15 | E-GEOD-59431 | biostudies-arrayexpress
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
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:Many different molecular mechanisms have been suggested to be associated with PML-RAR dependent transformation of haematopoietic progenitors. Here, we investigated the role of PML-RAR and RXR in the organization of epigenetic structures at a genome-wide level. We identified 2722 high confidence PML-RAR binding sites in the leukemic model cell line NB4 and found PML-RAR colocalization with RXR to the vast majority of these binding regions. Importantly, these results could be corroborated and extended in primary blast cells of two APL patients. Through genome-wide epigenetic studies we show that treatment with pharmacological doses of all-trans retinoic acid ATRA induces global alterations in active H3 acetylation and repressive H3K27me3, H3K9me3 and DNA methylation chromatin modifications. However at the PML-RAR/RXR binding sites, ATRA only induces changes in H3 acetylation. These H3 acetylation alterations triggered by the loss of PML-RAR/RXR binding affect H3 acetylation and RNA polymerase II occupancy at nearby genes. Our results suggest that PML-RAR/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for haematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RAR/RXR. Examination of PML, RARa and RXR binding sites in leukemic cells before and after ATRA treatment, association with transcription via RNAPII occupancy and with chromatin modifications.
2009-12-17 | E-GEOD-18886 | biostudies-arrayexpress
Project description:RARA haploinsufficiency is an invariable consequence of t(15;17) reciprocal translocations in acute promyelocytic leukemia (APL). Furthermore, retinoids and RARA activity have been implicated in hematopoietic self-renewal, lineage commitment and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis we crossed RARA+/- mice with mice expressing PML-RARA from the Cathepsin G locus (mCG-PR). We found that RARA haploinsufficiency cooperated with PML-RARA, only modestly influencing the pre-leukemic and leukemic phenotype. Bone marrow from mCG-PR+/- x RARA+/- mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation and an increased competitive advantage following transplantation. RARA haploinsufficiency did not alter mCG-PR dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; mCG-PR+/- x RARA+/- mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL arising in these mice was responsive to ATRA, and had virtually no differences in expression profiling compared to tumors arising in mCG-PR+/- x RARA+/+ mice. These phenotypes were dependent on PML-RARA activity, since they were not detected in RARA+/- mice in the absence of the mCG-PR transgene. These data show that RARA haploinsufficiency (like PML haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis and phenotype of APL in mice, but that PML-RARA is the driver of t(15;17) APL. RARA+/- mice were crossed with mice expressing PML-RARA from Cathepsin G locus (mCG-PR). Five leukemic mice were chosen from each of the mCG-PR+/-RARA+/- and mCG-PR+/-RARA+/+ strains and total RNA extracted from the spleen samples were analyzed using Affymetrics Mouse Exon 1.0 platform
2010-07-29 | E-GEOD-23291 | 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