BCP-ALL blasts are not dependent on CD19 expression for leukaemic maintenance.
Ontology highlight
ABSTRACT:
SUBMITTER: Weiland J
PROVIDER: S-EPMC4950966 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Acute myeloid leukaemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression. RUNX1-ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1-ETO expression is developmental stage specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit.
| S-EPMC4458875 | biostudies-literature
Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent malignancy in children and also occurs in adulthood. Despite high cure rates, BCP-ALL chemotherapy can be highly toxic. This type of toxicity can most likely be reduced by antibody-based immunotherapy targeting the CD19 antigen which is commonly expressed on BCP-ALL cells. In this study, we generated a novel Fc-engineered CD19-targeting IgG1 antibody fused to a single chain tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) domain (CD19-TRAIL). As TRAIL induces apoptosis in tumor cells but not in healthy cells, we hypothesized that CD19-TRAIL would show efficient killing of BCP-ALL cells. CD19-TRAIL showed selective binding capacity and pronounced apoptosis induction in CD19-positive (CD19+) BCP-ALL cell lines in vitro and in vivo. Additionally, CD19-TRAIL significantly prolonged survival of mice transplanted with BCP-ALL patient-derived xenograft (PDX) cells of different cytogenetic backgrounds. Moreover, simultaneous treatment with CD19-TRAIL and Venetoclax (VTX), an inhibitor of the anti-apoptotic protein BCL-2, promoted synergistic apoptosis induction in CD19+ BCP-ALL cells in vitro and prolonged survival of NSG-mice bearing the BCP-ALL cell line REH. Therefore, IgG1-based CD19-TRAIL fusion proteins represent a new potential immunotherapeutic agent against BCP-ALL.
| S-EPMC8232684 | biostudies-literature
Project description:Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
| S-EPMC4974466 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation which gives rise to the RUNX1/ETO fusion protein and initiates the most common form of human AML. To understand the molecular principles governing this differential action, we used the differentiation of mouse embryonic stem cells expressing an inducible RUNX1/ETO protein into blood cells as a traceable model combined with genome-wide analyses of transcription factor binding and gene expression. We found that RUNX1/ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1/ETO expression is stage-specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit.
2015-08-26 | GSE64589 | GEO
Project description:BackgroundActivation of free fatty acid receptor 2 (FFAR2) by microbiota-derived metabolites (e.g., propionate) reduces leukaemic cell proliferation in vitro. This study aims to test whether Ffar2 expression per se also influences leukaemia cell growth in vivo.MethodsBcr-Abl-expressing BaF cells were used as a leukaemia model and the role of Ffar2 was evaluated in Balb/c mice after lentiviral shRNA transduction.ResultsOur data formally establish that reduced leukaemic cell proliferation is associated with increased Ffar2 expression in vivo and in vitro. Going beyond association, we point out that decreasing Ffar2 expression fosters cancer cell growth in vitro and in vivo.ConclusionsOur data demonstrate the role of Ffar2 in the control of leukaemic cell proliferation in vivo and indicate that a modulation of Ffar2 expression through nutritional tools or pharmacological agents may constitute an attractive therapeutic approach to tackle leukaemia progression in humans.
| S-EPMC5672929 | biostudies-literature
Project description:B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.
| S-EPMC11010908 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation which gives rise to the RUNX1/ETO fusion protein and initiates the most common form of human AML. To understand the molecular principles governing this differential action, we used the differentiation of mouse embryonic stem cells expressing an inducible RUNX1/ETO protein into blood cells as a traceable model combined with genome-wide analyses of transcription factor binding and gene expression. We found that RUNX1/ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1/ETO expression is stage-specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit. High throughput sequencing data have been used to study RUNX1/ETO role in hematopoietic system
2015-08-26 | E-GEOD-64589 | biostudies-arrayexpress
Project description:B-cell precursor acute lymphoblastic leukemia (pre-B ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are needed. We evaluated the glycomes, transcriptomes and proteomes of the same samples using only about 10^6 cells for each assay. We found that the expression of many genes involved in glycosylation differ between MLL-r cells and normal controls: 61 of the 221 human glycosyltransferases were differentially expressed in MLL-r cells. The leukemia cell glycome and many proteins associated with glycan biosynthesis were also significantly changed compared to normal control precursor B-cells, indicating that the malignant phenotype of these cells could be regulated by such changes.
2021-10-13 | GSE176364 | GEO
Project description:Standard and inverted configuration small molecule OPV cells incorporating bathocuproine (BCP) as electron transport and exciton blocking layer is investigated, demonstrating that 2?mm2 standard and inverted cells display a maximum performance for BCP thicknesses of 10?nm and 1.5?nm, respectively. The reason for the different optimum BCP thicknesses for the two device configurations is the BCP-metal complex formed between the Ag electrode and the BCP layer in the standard configuration OPV devices. Interestingly, at optimum BCP thicknesses, the inverted OPV cells outperform the standard devices. Upon up-scaling of the device area of the cells from 2?mm2 to 10 and 100?mm2, device failure becomes prominent for the inverted OPV cells, due to aggregation of the evaporated BCP layer on the ITO surface. This demonstrates that although BCP can be adopted for efficient ETL in inverted configuration OPV devices on small scale, it is not suitable for device up-scaling due to severely decreasing device yields. In this work, a possible solution where an ultrathin layer of C70 is evaporated between the ITO and BCP layer is proposed. It is demonstrated that the proposed solution holds a strong potential to minimize the device failures of the BCP based inverted OPV cells to a significant extent, while maintaining good device performances.
| S-EPMC6105677 | biostudies-literature