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Evolution of monoclonal zebrafish Myc-induced T-ALL, assessed by copy number variant analysis

ABSTRACT: Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T-cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia propagating potential with time. We analyzed CNVs between monoclonal primary transplants and secondary transplants of clones that evovled increased leukemia propagating potential, and well as non-evovled clones with inherently high and low leukemia propagating potential. The goal of this study was to identify CNVs commonly assoicated with increased leukemia propagating cell frequency.

ORGANISM(S): Danio rerio

PROVIDER: GSE54482 | GEO | 2014/01/29

SECONDARY ACCESSION(S): PRJNA236611

REPOSITORIES: GEO

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Evolution of monoclonal zebrafish Myc-induced T-ALL, assessed by copy number variant analysis

Project description:Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T-cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia propagating potential with time. We analyzed CNVs between monoclonal primary transplants and secondary transplants of clones that evovled increased leukemia propagating potential, and well as non-evovled clones with inherently high and low leukemia propagating potential. The goal of this study was to identify CNVs commonly assoicated with increased leukemia propagating cell frequency. Myc-induced T-ALL were generated in syngenic CG1. Single T-ALL cells were transplanted into recipitent CG1, resulting in monoclonal T-ALL. In some instances, the monoclonal T-ALL were serially passaged. Leukemia propagating frequency was calculated for each T-ALL clone, at each passage. In this analysis, 9 primary T-ALL and 35 monoclonal T-ALL were individually run against a CG1 control.

2014-01-29 | E-GEOD-54482 | biostudies-arrayexpress

The side population enriches for leukemia propagating cell activity and Wnt pathway expression in zebrafish acute lymphoblastic leukemia.

Project description:Cancer stem cells have been strongly linked to resistance and relapse in many malignancies. However, purifying them from within the bulk tumor has been challenging, so their precise genetic and functional characteristics are not well defined. The side population assay exploits the ability of some cells to efflux Hoechst dye via ABC-transporters. Stem cells have increased expression of these transporters and this assay has been shown to enrich for stem cells in various tissues and cancers. This study identifies the side population within a zebrafish model of acute lymphoblastic leukemia and correlates the frequency of side population cells with the frequency of leukemia stem cells (more precisely referred to as leukemia propagating cells within our transplantation model). In addition, the side population within the leukemia evolves with serial transplantation, increasing in tandem with leukemia propagating cell frequency over subsequent generations. Sorted side population cells from these tumors are enriched for leukemia propagating cells and have enhanced engraftment compared to sorted non-side population cells when transplanted into syngeneic recipients. RNA-sequencing analysis of sorted side population cells compared to non-side population cells identified a shared expression profile within the side population and pathway analysis yielded Wnt-signaling as the most overrepresented. Gene set enrichment analysis showed that stem cell differentiation and canonical Wnt-signaling were significantly upregulated in the side population. Overall, these results demonstrate that the side population in zebrafish acute lymphoblastic leukemia significantly enriches for leukemia propagating cells and identifies the Wnt-pathway as a likely genetic driver of leukemia stem cell fate.

2021-12-10 | GSE123665 | GEO

Transcription profiling of CD38+ and CD38- cells derived from the same CLL patient reveals distinct gene expression signatures despite their monoclonal origin.

Project description:CD38 expression is an important prognostic marker in CLL with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38+ and CD38- chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38+ and CD38- CLL cells derived from the same patient were shown to be monoclonal by VH gene sequencing but despite this, CD38+ CLL cells possessed a distinct gene expression profile when compared with their CD38- sub-clones. Experiment Overall Design: These experiments compared the gene expression profile of CD38+ and CD38- sub-clones derived from 6 individual CLL patients.

2007-11-11 | E-GEOD-6321 | biostudies-arrayexpress

Targeting IRAK1 as a therapeutic approach for Myelodysplastic Syndrome

Project description:Myelodysplastic Syndromes (MDS) result from expansion of defective hematopoietic stem/progenitor clones. There is an urgent need to develop targeted therapies capable of eliminating the defective MDS clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS-propagating clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is selectively detrimental to MDS clones as normal CD34+ cells are preserved. Based on conclusions derived from an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment collaboratively and selectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS.

2013-04-25 | GSE46346 | GEO

A T-cell receptor targeting a shared neoantigen mediates elimination of primary human acute myeloid leukemia in vivo

Project description:This paper presents a T-cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine-kinase domain. TCRFLT3D/Y-redirected T cells selectively eliminated primary human AML cells harboring the D835Y mutation in vitro and in vivo. The TCRFLT3D/Y cells rejected both CD34+ and CD34- AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease negative levels, and eliminated primary CD34+ AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy towards selective elimination of clonally involved primary AML cells in vivo.

2023-08-28 | PXD043908 | Pride

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

Project description:The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

2024-04-01 | GSE257537 | GEO

Transcription profiling of human pre and pro B cells from patients with childhood acute lymphoblastic leudemia

Project description:This data was generated as part of a larger study in to the leukemic stem cell potential of sorted childhood ALL populations. This work has been submitted for publication with the following summary. "We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia. Human leukemic bone marrow was transplanted intrafemorally onto NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20 and CD34 were isolated from patient samples and engrafted mice before serial transplantation onto primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all the different maturational stages were able to reconstitute and re-establish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage appropriate genes. These observations lead to a new model for leukemia-propagating stem cells in childhood ALL." Diagnosis bone marrow specimens from children with acute lymphoblastic leukemia were FACS sorted into populations with surface expression CD34+CD19+ and CD34-CD19+. Expression analysis was performed to assess the developmental state of these two blast populations. These initial data have not been confirmed by RT PCR and should be viewed as preliminary. We are continuing with our work to further assess the transcriptional status of these populations.

2008-04-01 | E-MEXP-1522 | biostudies-arrayexpress

Affymetrix SNP array data for adult acute lymphoblastic leukemia samples

Project description:Copy number variation (CNV) and loss of heterozygosity (LOH) were investigated in adult Chinese patients with acute lymphoblastic leukemia (ALL), and these patients were screened for adult ALL prognostic genes.The most frequent CNVs are gain at chr13q, loss at chr6 and recurrent LOH at chr17p and 1p33. In Ph- B-ALL patients, the most frequent CNVs are gain at chr7, loss at chr9p and recurrent LOH at chr15q. In T-ALL, the most frequent CNVs are gain at chr20 and 7q, loss at chr2p and recurrent LOH also at chr15q.

2015-01-01 | GSE57018 | GEO

The effects of knockdown of PML by different individual siRNAs in HUVEC cells

Project description:To study the potential target genes regulated by PML in endothelial cells, we carried out siRNA-mediated knockdown of PML in HUVEC cells. To eliminate the off-target effects of siRNAs, we utilized two different siRNAs. Only the genes changed in the same pattern following both siRNAs transfection are considered as potential PML-knockdown responsive genes. The experiment is one-factor (siRNA) with three ranks (siCtrl, siPML-1, siPML-2). We included technical duplicates for each sample. To minimize systemic errors assoicated with technique, we distributed the duplicates on two different microarray chips.

2012-05-30 | E-GEOD-29238 | biostudies-arrayexpress

Copy Number Variation at 16p11.2 Imparts Transcriptional Alterations in Neural Development in an hiPSC-derived Model of Corticogenesis

Project description:Microdeletions and microduplications of the 16p11.2 chromosomal locus are implicated in a collection of neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations of these phenotypes, we generated 65 clones of human induced pluripotent stem cells (hiPSCs) from 13 individuals with 16p11.2 copy number variations (CNVs) and made each clone available by request from the Simons Foundation Autism Research Initiative (SFARI). Here we report on pluripotency, vector silencing, CNV breakpoint location, inter-clonal relatedness, and differentiation capacity for a majority of the available hiPSC clones. Comprehensive demographic and diagnostic data were collected and tabulated to facilitate investigation across a spectrum of pathologies. We demonstrate a customizable bioinformatic strategy for enhanced detection of the effects of episomal reprogramming and use this tool to identify a subset of clones free of off-target effects on neural progenitor gene transcription and phenotypic variation . With cortical neural progenitor cells (NPCs) derived from these hiPSCs, we identified a set of genes modulated by 16p11.2 deletion that precede morphological abnormalities reported at more mature developmental stages. This publicly available resource of 65 human hiPSC clones will serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

2020-12-03 | GSE144736 | GEO

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