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PDX models of relapsed pediatric AML preserve global gene expression patterns and reveal therapeutic targets

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252945 | GEO | 2025/01/09

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

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PDX models of relapsed pediatric AML preserve global gene expression patterns and reveal therapeutic targets

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