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Assessment of ability of hTSLP to maintain primary CRLF2 B-ALL cells in a xenograft model in a state more similar to the parent leukemia

ABSTRACT: Xenograft models represent an excellent method for expanding primary leukemias, but their ability to preserve the gene expression profile of the parent leukemia may also depend on providing microenvironmental factors that are not cross-reactive between human and mouse. Here we focused on leukemias with a CRLF2 mutation, and the ability of human TSLP to stimulate these cells. Three different classes of samples were analyzed. 1) The primary leukemia sample without any culture or treatment 2) Xenograft samples (2) of the primary leukemia that were exposed to TSLP in vivo for 2 weeks, 9 weeks post-engraftment and 3) Xenograft samples (2) of the primary leukemia that were NOT exposed to TSLP in vivo for 2 weeks, 9 weeks post-engraftment.

ORGANISM(S): Homo sapiens

SUBMITTER: Kimberly Payne

PROVIDER: E-GEOD-74339 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Assessment of ability of hTSLP to maintain primary CRLF2 B-ALL cells in a xenograft model in a state more similar to the parent leukemia

Project description:Xenograft models represent an excellent method for expanding primary leukemias, but their ability to preserve the gene expression profile of the parent leukemia may also depend on providing microenvironmental factors that are not cross-reactive between human and mouse. Here we focused on leukemias with a CRLF2 mutation, and the ability of human TSLP to stimulate these cells.

2015-12-31 | GSE74339 | GEO

TSLP-Induced Gene Expression Signature in Primary CRLF2 B-ALL

Project description:The cytokine TSLP stimulates in vitro proliferation of human fetal B cell progenitors. Genetic alterations that cause overexpression of the TSLP receptor component, CRLF2, lead to B cell acute lymphoblastic leukemia (CRLF2 B-ALL) with poor outcome. The in vivo role of TSLP in normal human B cell development and its contribution to CRLF2 B-ALL are unknown. In classic xenograft models CRLF2-mediated signaling is unlikely to be activated by mouse TSLP, based on data from engineered cellular models. Here, we show that mouse TSLP does not induce activation of the CRLF-2 downstream pathways (JAK/STAT and AKT/mTOR) that are induced by human TSLP (hTSLP) in CRLF2 B-ALL cells. Based on this, we developed a novel human-mouse xenograft model system comprised of mice that produce hTSLP (+T mice) to activate human CRLF2-mediated signaling and mice that lack hTSLP (–T mice). Normal serum levels of hTSLP were achieved in +T mice, while hTSLP was undetectable in –T mice. hTSLP produced by stroma induced JAK/STAT and AKT/mTOR pathway activation and showed functional in vivo effects on normal human B cell progenitors and primary CRLF2 B-ALL cells. Whole genome microarray of primary CRLF2 B-ALL showed an induction of mTOR regulated gene expression and preservation of TSLP responsiveness in cells expanded in +T mice as compared to –T mice.

2016-05-03 | GSE65274 | GEO

Homo sapiens

Project description:TSLP-Induced Gene Expression Signature in Primary CRLF2 B-ALL

| PRJNA273609 | ENA

Thymic stromal lymphopoietin modulates T cell response to improve cardiac repair post-myocardial infarction

Project description:The inflammatory response is associated with cardiac repair and ventricular remodeling after myocardial infarction (MI). The key inflammation regulatory factor thymic stromal lymphopoietin (TSLP) plays a critical role in various diseases. However, its role in cardiac repair after MI remains uncertain. In this study, we elucidated the biological function and mechanism of action of TSLP in cardiac repair and ventricular remodeling following MI. Wild-type and TSLP receptor (TSLPR)-knockout (Crlf2-/-) mice underwent MI induction via ligation of the left descending artery. TSLP expression was upregulated in the infarcted heart, with a peak observed on day 7 post-MI. TSLP expression was enriched in the cardiomyocytes of infarcted hearts, with the highest expression observed in dendritic cells. Crlf2-/- mice exhibited significantly reduced survival and worsened cardiac function, increased interstitial fibrosis and cardiomyocyte cross-sectional area, and reduced CD31+ staining, with no change in the proportion of apoptotic cardiomyocytes within the border zone. Mechanistically, a reduction in regulatory T cells and more innate immune cells and their subsets were observed in the infarcted hearts of Crlf2-/- mice, accompanied by a systemic reduction in T cell activation and proliferation. Simultaneously, RNA sequencing analysis of the infarcted hearts revealed significant downregulation of genes in Crlf2-/- mice. Our findings indicate that TSLP plays a pivotal role in regulating T cell responses, specifically T regulatory cells, thus promoting cardiac repair, which may provide a potential novel therapeutic approach for managing heart failure after MI.

2024-09-21 | GSE265931 | GEO

Combined proteomics and CRISPR-Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo

Project description:Acute leukemias represent deadly malignancies which require better treatment. As challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR-Cas9 pipeline in PDX models in vivo. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as essential vulnerability required for survival and growth of different types of acute leukemias in vivo and reconstitution assays in PDX models proved the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. These findings identify ADAM10 as attractive therapeutic target for future treatment of acute leukemias.

2023-07-24 | PXD036223 | Pride

Assesment of gene expression upon AF10 deletion in MLL-AF9 secondary leukemia

Project description:Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Primary MLL-AF9 leukemias in the AF10 floxed background (homozygous) were transduced with MSCV-IRES-tdTomato (MIT) or the Cre recombinase expressing MIT vector, cells were sorted and injected into secondary recipient mice to generate Af10 floxed (MIT) or deleted (CRE) leukemias. BM cells fresly harvested from these leukemias were sorted for tdTomato expression and used for microarrays. BM cells from Hoxa9-Meis1 transduced primary leukemias were used for comparison.

2014-09-08 | E-GEOD-54499 | biostudies-arrayexpress

Discovery of TF-gene regulatory interactions identifies new targets in CRLF2-overexpressing B-ALL

Project description:We analyzed the impact of CRLF2 overexpression on transcriptional and chromatin accessibility landscape in primary patient samples and cell lines in B-cell leukemia.

2023-01-01 | GSE162342 | GEO

Homo sapiens

Project description:Assessment of ability of hTSLP to maintain primary CRLF2 B-ALL cells in a xenograft model in a state more similar to the parent leukemia

| PRJNA299771 | ENA

RNA sequencing of murine Nup98-Phf23-driven pro-B1 ALL

Project description:B-1 and B-2 lymphocytes are derived from distinct developmental pathways, and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to the majority of murine B- cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice. The immunophenotype (Lin- B220 - CD19+ AA4.1+) was identical to B-1 progenitor cells, and VH gene usage was skewed toward 3’ V regions, similar to murine fetal liver B-cells. We performed RNA sequencing and determined that the expression profile of these leukemias was most similar to fetal liver pro B fraction BC, a known source of B-1 B cells, further supporting a B-1 progenitor origin of these leukemias. The NP23 B-1 progenitor ALLs acquired spontaneous mutations in both Bcor and Jak pathway (Jak1/2/3 and Stat5a) genes, supporting a hypothesis that mutations in three critical pathways (stem cell self-renewal, B-cell differentiation, and cytokine signaling) collaborate to induce B-cell precursor (BCP) ALL. Finally, the Tslp cytokine is required for murine B- 1 development, and chromosomal rearrangements resulting in overexpression of the TSLP receptor (CRLF2) are present in some high risk BCP ALL patients (referred to as CRLF2r ALL). Gene expression profiles of NP23 pro-B1 ALL were more similar to CRLF2r ALL than non-CRLF2r ALL, and analysis of VH gene usage from CRLF2r ALL patients demonstrated preferential usage of VH regions used by human B-1 B-cells, leading to the suggestion that this subset of BCP ALL patients have a malignancy of B-1, rather than B-2 B-cell origin.

2018-10-10 | GSE104769 | GEO

Leukemia reconstitution in vivo is driven by cells in early cell cycle and low metabolic state

Project description:To characterize LICs in ALL irrespective of surface markers expression, we investigated leukemia initiating activities of cellular subfractions of patient-derived xenograft BCP-ALL cells sorted according to different cell cycle phases (i.e. G0/G1 and G2/M) followed by transplantation onto NOD/SCID mice. All cell fractions led to leukemia engraftment indicating LIC activity irrespective of cell cycle stage. Most importantly, cells isolated from G0/G1 cell cycle phases led to early leukemia engraftment in contrast to cells from late cell cycle (G2/M). To further characterize cells with different engraftment potential in vivo, we analyzed the gene expression profiles of early (G1b early) and late (G2/M) engrafting cells.

2018-03-18 | GSE71836 | GEO

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