Global RNA-sequencing of a pediatric AML primary sample treated with Tamibarotene or vehicle
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE155559 | GEO | 2021/08/01
REPOSITORIES: GEO
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Project description:Somatic mutations are rare in pediatric AML (pAML), indicating alternate strategies are needed to identify new, pediatric AML-specific, druggable targets. We defined the enhancer landscape of 22 pAML patient samples and observed many known leukemia regulators are SE-associated in pAML. We confirmed that the expression of several of these SE-associated genes correlated with gene expression by RNA-Seq. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort and present in all cyto/molecular subtypes tested, totaling 64% of the pAML samples. RARA SE-positive pAML cell lines and samples had higher RARA mRNA levels than RARA SE-negative samples and also were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with halted proliferation and upregulated retinoid target genes. Tamibarotene prolonged survival and suppressed the leukemia burden of a RARA SE-positive pAML patient-derived xenograft (PDX) mouse model compared to a RARA SE-negative PDX. These data demonstrate the utility of leveraging chromatin regulation to identify new dependencies in pediatric AML and specifically lay the preclinical foundation for a tamibarotene trial in children with relapsed/refractory AML.
2021-08-01 | GSE176559 | GEO
Project description:Somatic mutations are rare in pediatric AML (pAML), indicating alternate strategies are needed to identify new, pediatric AML-specific, druggable targets. We defined the enhancer landscape of 22 pAML patient samples and observed many known leukemia regulators are SE-associated in pAML. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort and present in all cyto/molecular subtypes tested, totaling 64% of the pAML samples. RARA SE-positive pAML cell lines and samples had higher RARA mRNA levels than RARA SE-negative samples and also were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with halted proliferation and upregulated retinoid target genes. Tamibarotene prolonged survival and suppressed the leukemia burden of a RARA SE-positive pAML patient-derived xenograft (PDX) mouse model compared to a RARA SE-negative PDX. These data demonstrate the utility of leveraging chromatin regulation to identify new dependencies in pediatric AML and specifically lay the preclinical foundation for a tamibarotene trial in children with relapsed/refractory AML.
2021-08-01 | GSE155558 | GEO
Project description:AML cell lines were treated with either vehicle or SY-1425 (tamibarotene), a potent and selective agonist of retinoic acid receptor alpha (RARa), and assayed by microarray expression analysis.
2017-08-15 | GSE97331 | GEO
Project description:Global RNA-sequencing of a pediatric AML primary sample treated with Tamibarotene or vehicle
| PRJNA650298 | ENA
Project description:Pediatric AML is an aggressive hematological malignancy associated with distinctive genomic features. We employed RNA-seq to study fusion genes and clinically relevant gene expression patterns in pediatric AML patients.
2023-05-02 | GSE222814 | GEO
Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.
2015-05-07 | E-GEOD-52891 | biostudies-arrayexpress
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD041749 | Pride
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD040953 | Pride
Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients.
2015-05-07 | GSE52891 | GEO
Project description:Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia, that is generally driven by PML-RARA, resulting from a balanced chromosomal translocation t(15;17) (q24.1;q21.2). However, approximately 2% of APL patients carry other variants of RARA-fusions, which pose challenges for diagnosis and treatment. Here, we report a novel t(14;17) translocation in an APL patient that gave rise to a new fusion gene, STRN3-RARA. STRN3 forms a complex called the striatin-interacting phosphatase and kinase (STRIPAK), which couples kinases to protein phosphatase 2A and regulates their activities. Like other APL patients with RARA-variants, this patient quickly relapsed after the initial response to all-trans retinoic acid (ATRA) treatment. Mechanistically, we demonstrated that STRN3-RARA, in cooperating with UTX deficiency, which was mutated in the patient, drove APL formation in mice. Additionally, we found that STRN3-RARA cells were specifically susceptible to the TNFα pathway. Inhibition of this pathway by cepharanthine, an FDA-approved drug, effectively suppressed the growth of U937 cells with STRN3-RARA expression, as well as relapsed APL cells from the patient. Taken together, our study identified a new APL fusion gene, STRN3-RARA, and validated it as a functional APL driver, providing insight into the diagnosis and treatment of non-classic APL patients.
2024-04-23 | GSE239350 | GEO