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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.

2023-12-31 | GSE237057 | GEO

Environmental-mediated vincristine drug resistance of human precursor B-acute lymphoblastic leukemia (pre-B ALL)

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

Early measurable residual disease dynamics and B cell receptor reconstitution following venetoclax and obinutuzumab in chronic lymphocytic leukemia

Project description:In chronic lymphocytic leukemia, measurable residual disease (MRD) depth following fixed-duration treatment is associated with progression-free survival (PFS). Often, MRD is reported as a static parameter, but successive MRD measurements may more accurately capture MRD dynamics and reveal valuable prognostic information. We used our recently developed IGHV leader-based NGS assay to measure MRD at four timepoints in 60 patients treated in the HOVON-139/GIVE trial, in which previously untreated patients received one year induction treatment with obinutuzumab and venetoclax, followed by randomization to consolidation treatment with venetoclax or MRD-conditional consolidation. Induction treatment resulted in MRD undetectability (<10-5) in 93% of assessed patients, with 85% and 74% of patients retaining MRD undetectability at six and twelve months after randomization. Uniquely, we measured MRD at a very early timepoint, during the fourth week of venetoclax ramp-up after obinutuzumab pre-induction. Here, MRD levels showed large interindividual variation, and, importantly, were associated with the probability of achieving MRD undetectability after induction treatment, MRD conversion after randomization and PFS. Additionally, the IGHV leader-based NGS assay allows characterization of the healthy background IGHV repertoire. Of note, venetoclax consolidation treatment, compared to no consolidation treatment, significantly impaired polyclonal IGHV repertoire reconstitution after induction treatment with venetoclax and obinituzumab.

2024-03-01 | GSE225043 | GEO

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters

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.

2022-08-15 | GSE210916 | GEO

Measuring Minimal Residual Disease beyond 10-5 through IGHV leader-based NGS increases Prognostic Discrimination in Chronic Lymphocytic Leukemia

Project description:The sensitivity of conventional techniques for the quantification of minimal/measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is limited to MRD 10-4. Measuring MRD <10-4 could help to further distinguish between CLL patients with durable remission and those at risk of early relapse. We here present a novel, academically developed IGHV leader-based next-generation sequencing (NGS) assay for the quantification of MRD in CLL. We demonstrate, based on measurements in contrived MRD samples, that the linear range of detection and quantification of our novel assay reaches beyond MRD 10-5. If provided with sufficient DNA input, MRD can even be detected down to MRD 10-6. There was high inter-assay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative PCR (r=0.92, [95%CI 0.86-0.96]) and droplet digital PCR (r=0.93, [95%CI 0.88-0.96]) on contrived MRD samples. In a cohort of 37 patients from the CLL11 trial, using MRD 10-5 as a cut-off, MRD undetectability was associated with superior progression-free survival (PFS) and time to next treatment. Importantly, deeper MRD measurement allowed for additional stratification of patients with MRD <10-4 but ≥10‑5. Whereas the PFS of these patients was significantly shorter, compared to patients with MRD <10-5 (HR 4.9, [95%CI 1.3-17.9], P=0.017), their PFS was superior to those with MRD ≥10‑4 (HR 0.18, [95%CI 0.06-0.46], P<0.001). These results clearly demonstrate the clinical utility of the novel IGHV-leader based NGS assay.

2021-11-13 | GSE188587 | GEO

Identification of rare, dormant and therapy resistant stem cells in acute lymphoblastic leukemia

Project description:Tumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression profiling revealed their similarity to primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD). Therapeutically adverse characteristics were reversible, as resistant, dormant cells became sensitive to treatment and started proliferating when dissociated from the in vivo environment. Our data suggest that ALL patients might profit from therapeutic strategies that release MRD cells from the niche.

2016-12-06 | GSE83142 | GEO

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