PDX models of relapsed pediatric AML preserve global gene expression patterns and reveal therapeutic targets
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1063296 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Patient-derived xenograft (PDX) models are commonly used for preclinical evaluation of targeted therapies. It is important to consider the fidelity with which these systems recapitulate the patient disease state. Currently, there is little information regarding how well pediatric AML PDXs mimic the global gene expression found in patients. Here we analyzed RNAseq data from a diverse series of high-risk pediatric AML PDXs, separately and compared to primary patient data. Unsupervised clustering of PDX data resulted in segregation according to KMT2A (MLL) status. Combined analysis showed PDX samples aligned with patient samples harboring similar genetics. Among KMT2A rearranged samples, we observed strong correlation of expression levels of nearly all expressed transcripts. Furthermore, matched patient/PDX pairs showed strong concordance, suggesting retention of sample-specific gene expression. Interestingly, our analysis uncovered previously unidentified cryptic CBFA2T3-GLIS2 rearrangement in two PDX models. Based on high BCL2 mRNA in these models, we tested the efficacy of venetoclax in combination with chemotherapy. While standard daunorubicin/ara-C treatment failed to produce benefits, CPX-351 decreased disease burden and prolonged survival, particularly when combined with venetoclax. These results validate PDX modeling of high-risk pediatric AML and highlight this system's utility for pre-clinical therapeutic discovery, especially for rare subtypes of disease.
2025-01-09 | GSE252945 | 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: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:Genome wide DNA methylation profiling of blood and bone marrow of Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia. The Illumina Infinium EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across over 860,000 CpGs.
2023-12-31 | GSE225239 | GEO
Project description:Relapsed Acute Lymphoblastic Leukemia (ALL): Genomic Analysis in Pediatric Patients
| PRJNA311978 | ENA
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:DNA methylation of Relapsed/Refractory AML
| PRJNA934390 | ENA
Project description:Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is MDM2-independent and exhibits synergistic in vitro and in vivo anti leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.
2024-04-10 | GSE213766 | GEO
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:The majority of relapsed acute myeloid leukemia (AML) patients still succumb to disease despite improvements in therapy. We present landscapes of pharmacologic sensitivity for 22 AML patient-derived xenograft (PDX) models together with genomic and transcriptomic profiles. First, we used ex vivo dynamic BH3 profiling (DBP) to segregate PDXs according to prior treatment status and accurately predicted in vivo efficacy of drugs with varying mechanisms of action. We next selected in vivo acquired resistance to single agents of distinct mechanisms, which caused broad chemoresistance across all models associated with a reduction in mitochondrial apoptotic priming. DBP could identify drugs with persistent in vivo activity even in these resistant models. Using RNA-seq, we found conserved gene expression signatures defining relapsed phenotypes common to mechanistically distinct agents targeting FLT-3, BCL2, IAPs, and BRD-4. We replicated drug-response patterns from PDX models in primary and relapsed AML patients, demonstrating the clinical feasibility of such approach
2024-02-15 | GSE237794 | GEO