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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26268 | GEO | 2011/08/01

SECONDARY ACCESSION(S): PRJNA135061

REPOSITORIES: GEO

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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. Comparison of bone marrow-derived human- and mouse-derived leukemia samples.

2011-07-31 | E-GEOD-26268 | biostudies-arrayexpress

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

Cell-free DNA 5-hydroxymethylcytosine is highly sensitive for MRD assessment in acute myeloid leukemia

Project description:Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). However, MRD cannot be detected in many patients using current methods. We developed a highly sensitive 5-hydroxymethylcytosine (5hmC) signature in cell-free DNA by analyzing 115 AML patients and 86 controls. The 5hmC method detected MRD in 20 of 29 patients with negative MRD by multiparameter flow cytometry and 11 of 14 patients with negative MRD by molecular methods. MRD detection by the 5hmC method was significantly associated with relapse-free survival. This novel method can be used in most AML patients and may significantly impact AML patient management.

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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.

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Project description:First-line treatment for pre-B acute lymphoblastic leukemia (pre-B ALL) typically encompasses a period of so-called induction therapy in which the patient is treated for 28 days with chemotherapy to induce a remission. A bone marrow sample is subsequently taken to determine the number of remaining leukemia cells, which are called minimal residual disease (MDR). MRD is a key prognostic factor, with higher MRD levels predicting worse outcome for patients. Induction therapy usually is able to drastically reduce the number of leukemic cells but chemoresistance, as first detected by higher MRD levels, remains a major clinical problem. MRD persists not only by leukemia cell-intrinsic mechanisms such as clonal selection and genetic changes, but also through protective interactions of the leukemia cells with the surrounding supporting stroma. This mechanism of drug resistance has been named environment-mediated drug resistance (EMDR) and is a general route through which MRD cells, regardless of underlying genetics of the leukemia cells, can persist after chemotherapy. The EMDR component contributing to the persistence of MRD leukemia cells can be studied in tissue culture models by treating leukemia cells with a non-lethal drug dose in the presence of stromal cell protection. Here we analysed the transcriptome of a PDX-derived human pre-B ALL cell line co-cultured with OP9 stromal cells as they developed drug insensitivity against the chemotherapeutic drug vincristine.

2023-02-28 | GSE176366 | GEO

Transcription profiling by array of diagnosis and relapse specimens of paediatric patients with acute lymphoblastic leukaemia (ALL) to identify mechanisms and pathways of therapy failure

Project description:Gene expression profiles were compared between diagnosis and relapse specimens of paediatric patients with acute lymphoblastic leukaemia (ALL) to identify mechanisms and pathways of therapy failure. The following descriptions provide further information on the annotations applied in this submission: Day 7 MRD- Minimal residual disease (MRD) measured at Day 7 after treatment initiation. Day 14 MRD- MRD measured at day 14 after treatment initiation. End of Induction MRD- MRD at the end of remission induction therapy. Event- Clinical event that is used to interpret patient outcome and used to determine relapse status. Relapse status- The relapse status of the patient which is used to model kaplan-meier survival curves in the related manuscript. Status 0 indicates non-relapse status (patient didn't relapse within time monitored), and 1 indicates relapse. Relapse-Free Survival- The length of time that the patients were relapse-free, or the length of time they were studied for, if they did not relapse. Paired Specimen- Many of the specimens in this study were diagnosis and relapse specimens from the same patient (i.e. Specimens taken at different times). This factor indicates which of the specimens were matched to each other in this way i.e. Which came from the same patient.

2012-07-13 | E-MTAB-1216 | biostudies-arrayexpress

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2024-03-01 | GSE225043 | GEO

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Project description:Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells, called measurable residual disease (MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing tri-methylation of histone 3 lysine 27 (H3K27) and H3K4. Moreover, within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking upregulation of doxorubicin-induced H3K27me3 or H3K4me3. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by inhibition of KDM6. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced the response to chemotherapy in vivo. Together, our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.

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