AML cell line expression response to SY-1425 (tamibarotene)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97331 | GEO | 2017/08/15
SECONDARY ACCESSION(S): PRJNA381423
REPOSITORIES: GEO
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Project description:The purpose of this study was to assess the global transcriptional changes in a pediatric AML primary sample treated with Tamibarotene. This patient sample has a retinoic acid receptor alpha (RARA) super-enhancer, which is correlated with higher RARA mRNA levels and increased sensitivity to Tamibarotene in vitro and in vivo (Patient-derived xenograft mouse model).
2021-08-01 | GSE155559 | 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: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:AML cell line expression response to SY-1425 (tamibarotene)
| PRJNA381423 | ENA
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:To identify the top 20 up-regulated genes in CD34+ cells from AML patients in comparison with healthy donors, we examined the microarray gene expression profile of CD34+ blasts from patients with newly diagnosed AML vs CD34+ normal cells from healthy donors. Despite the fact that combined therapy of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapy dramatically improves the prognosis of patients with APL, these regimens can cause systemic infections and secondary leukemias. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing its sumoylation, ubiquitylation and degradation. This represses PML nuclear body assembly, p53-mediated senescence, cell differentiation, and supports cellular self-renewal. Genetically inhibiting Trib3 expression or disturbing the TRIB3/PML-RARa interaction produces potent therapeutic efficacy against APL and has synergic anti-APL effects when used in combination with ATRA or ATO by promoting PML-RARa degradation and PML expression. Our study provides new insight into APL pathogenesis and a new therapeutic option against APL.
2017-05-12 | GSE90062 | GEO
Project description:Global RNA-sequencing of a pediatric AML primary sample treated with Tamibarotene or vehicle
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Project description:Primary human AML cells (newly diagnosed, prior to treatment initation) were obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. AML blasts were treated with FLT3 inhibitor gilteritinib (or DMSO vehicle control) at 10 nM concentration for 6 h, followed by harvest for LC/MS.
2022-08-25 | PXD034080 | Pride