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Unknown,Transcriptomics,Genomics,Proteomics

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Donor-specific NK cells exert potent cytolytic effector functions against patient-specific leukemic blasts in an IL-7 and IL-15 supplemented humanized NOD/SCID/IL2Rγnull mouse model

ABSTRACT: Surrogate models have so far been missing that might allow the evaluation of graft-versus-leukemia effects in an individualized donor-patient-specific context. We here describe the generation of a NOD/SCID/IL2Rγnull (NSG) leukemia mouse model that ideally resembles the biology of miscellaneous patient-specific leukemias. Following transfer of patient-derived blasts into NSG mice, various forms of pediatric haematological malignancies readily engrafted NSG recipients and NSG-derived leukemic cells indeed resembled the individual leukemia with respect to phenotype, chromosomal aberrations, transcriptome and MRD marker expression. Comparison of bone marrow-derived human- and mouse-derived leukemia samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Bonin

PROVIDER: E-GEOD-26268 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Donor-specific NK cells exert potent cytolytic effector functions against patient-specific leukemic blasts in an IL-7 and IL-15 supplemented humanized NOD/SCID/IL2Rγnull mouse model

Project description:Surrogate models have so far been missing that might allow the evaluation of graft-versus-leukemia effects in an individualized donor-patient-specific context. We here describe the generation of a NOD/SCID/IL2Rγnull (NSG) leukemia mouse model that ideally resembles the biology of miscellaneous patient-specific leukemias. Following transfer of patient-derived blasts into NSG mice, various forms of pediatric haematological malignancies readily engrafted NSG recipients and NSG-derived leukemic cells indeed resembled the individual leukemia with respect to phenotype, chromosomal aberrations, transcriptome and MRD marker expression.

2011-08-01 | GSE26268 | GEO

Human IL-6 fosters long-term engraftment of human patient derived myeloma cells in immunodeficient mice

Project description:Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed blood M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Singe cell RNAseq analyses showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma-engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish that NSG+hIL6 mice provide an effective patient derived xenograft model for study and preclinincal drug development for myeloma and related plasma cell disorders.

2024-10-14 | GSE246140 | GEO

Engraftment of limited numbers of pediatric leukemia into NOD/SCID/IL2Rcg-null mice enables surrogate markers for clinical outcome

Project description:Cultured immortalized cell lines have been extensively used to study the characteristics of various malignant stem cell clones and to optimize new treatment strategies. Nonetheless, the usefulness of such in vitro systems to recapitulate primary disease proved to be limited. Therefore, the design of more meaningful pre-clinical in vivo models ideally utilizing primary patient-derived material is of critical importance. In this context, the recently described NOD.Cg-Prkdcscid IL2rgtmWjl/Sz (NSG) mouse strain has been reported to sustain superior engraftment rates of patient-derived acute lymphatic and myeloid leukemic samples. However, limited data exist whether NSG-derived blasts retain their leukemogenecity over successive mouse generations and whether characteristics of this mouse model will indeed allow correlation to clinical parameters. In the present study, we thus engrafted NSG mice with 18 different pediatric B cell precursor ALL, AML and T-ALL samples and could demonstrate that NSG-derived blasts retained their leukemogenic profile with respect to immune-phenotype, chromosomal aberrations, transcriptome, flowcytometric- and PCR-minimal residual disease (MRD) marker expression. Moreover, the extent of leukemic engraftment and the overall survival of NSG mice highly correlated with the individual prognosis of pediatric B cell precursor ALL, AML and T-ALL patients. Thus, we here report on a complex in vivo model that provides a valuable tool for studying the heterogeneity of leukemic disease and for improving patient-tailored leukemia-targeting strategies . In the present study, we thus engrafted NSG mice with 18 different pediatric B cell precursor ALL, AML and T-ALL samples and could demonstrate that NSG-derived blasts retained their leukemogenic profile with respect to immune-phenotype, chromosomal aberrations, transcriptome, flowcytometric- and PCR-minimal residual disease (MRD) marker expression.

2012-03-31 | E-GEOD-35504 | biostudies-arrayexpress

Engraftment of limited numbers of pediatric leukemia into NOD/SCID/IL2Rcg-null mice enables surrogate markers for clinical outcome

2012-04-01 | GSE35504 | GEO

Sequencing of patient-derived xenografts in NSG mice

Project description:Variant analysis of patient-derived xenografts in NSG mice

| PRJEB52345 | ENA

RNA-seq expression analysis of patient-derived xenografts in NSG mice

Project description:RNA-seq expression analysis of patient-derived xenografts in NSG mice

| PRJEB38645 | ENA

Primary human CD34+ cells for modeling ETO2-GLIS2 leukemogenesis - Bulk RNAseq

Project description:Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, a hallmark of dismal prognosis. We induced expression of ETO2::GLIS2 in primary human fetal and cord blood CD34+ hematopoietic cells and obtained bulk transcriptomes after in vitro cultures or in vivo engraftment and leukemia development in immunodeficient recipients (NSG or NSG-SGM3=NSG-S).

2024-10-08 | E-MTAB-14131 | biostudies-arrayexpress

Stranded RNA-seq expression analysis of patient-derived xenografts in NSG mice

Project description:Stranded RNA-seq expression analysis of patient-derived xenografts in NSG mice

| PRJEB38807 | ENA

Adverse stem cell features in a single AML sample predict clinical outcome in AML patient cohorts

Project description:Patients with acute myeloid leukemia (AML) suffer dismal prognosis and the most adverse subpopulation within each tumor determines patient’s prognosis. To better understand challenging features in AML, we studied individual stem cells from a single AML sample, complementing genomic with in vivo functional studies. Primary tumor cells from an AML patient’s first and second relapse were transplanted into NSG mice to establish serially transplantable patient derived xenografts (PDX). In an innovative approach, twelve derivative PDX clones were generated thereof, each derived from a single AML stem cell as proven by molecular barcoding, and were color-marked to facilitate multiplex competitive in vivo assays. PDX clones consisted of four different genomic clusters; one cluster displayed resistance against Cytarabine treatment, while two other clusters harbored increased stem cell potential, indicating that stemness and treatment resistance had evolved independently in the sample. In vivo functional data correlated closely with the phylogenetic tree calculated from exome data. The Cytarabine-resistant cluster was characterized by a distinct gene expression profile, and a score thereof predicted outcome in large clinical patient data cohorts. Taken together, we provide proof of concept that intra-sample heterogeneity mimics inter-sample heterogeneity in AML. Stem cell disparities within a single sample allow insights into adverse characteristics of general importance for AML.

2022-04-04 | PXD026296 | Pride

Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8<sup>+</sup> cytolytic T cells.

Project description:Recently, the role of lactate as merely an end product of cancer cell metabolism has been reassessed. Lactate has been implicated in more biological processes than previously understood and drives tumor progression. Here, we demonstrated that the bone marrow lactate concentrations in acute myeloid leukemia (AML) patients were substantially higher than those in their healthy control counterparts. Moreover, AML blasts from bone marrow expressed significantly higher lactate dehydrogenase-A (LDHA) levels. Further studies revealed that LDHA expression was regulated through the HIF1α pathway. Elevated lactate levels were indicative of alterations in CD8+ T cell cytolytic phenotype and activity. An in vitro study showed that the lactate treatment group had significantly higher percentages of CD8+ TEM and CD8+ TEMRA cells as well as higher PD-1 expression in these cells than the control group. Lactate induced the loss of the effector function of CD8+ T cells by altering lytic granule exocytosis. T cell dysfunction is characterized by an increase in terminally differentiated phenotypes, sustained expression of PD-1, and accelerated decline of cytolytic competence. Moreover, the TOX gene was found to be correlated with lactate production and implicated in CD8+ T cell dysfunction. AML patients in complete remission after chemotherapy had markedly lower lactate concentrations, reduced CD8+ TEM and CD8+ TEMRA cells and PD-1 expression, and increased perforin and granzyme B. However, no difference was found in the relapsed patients. The study presented here has established lactate as a predictive biomarker for patient response to antitumor therapies and demonstrated that targeting this gene in AML patients could be a meaningful precision therapeutic strategy.

| S-EPMC8640829 | biostudies-literature

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