Gene Expression Data from U937T:PLZF-RARa Inducible Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE18476 | GEO | 2009/11/30
SECONDARY ACCESSION(S): PRJNA120211
REPOSITORIES: GEO
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Project description:The PLZF-RARa fusion oncoprotein is overexpressed in the t(11;17) subtype of acute promyelocytic leukemia. Gene expression microarrays were used to identify genes involved in leukemic transformation. We used microarray to detect gene expression changes induced by the PLZF-RARa fusion oncoprotein in the U937 cell line Experiment Overall Design: The U937T:PLZF-RARa cell line was engineered to express PLZF-RARa upon tetracycline removal. PLZF-RARa was induced for 48hr and RNA was extracted and hybridized to Affymetrix HGU133Plus2.0 Chips
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Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
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Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
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Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
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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.
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