Filters
Technology
Platform
SRP071580
Mus musculus
14 Downloadable Samples
NextSeq 500
Description
Acute myeloid leukemia (AML) is associated with poor prognosis, and there is a strong need to develop new therapeutic strategies to improve treatments. We performed a cytokine screen with 114 recombinant proteins to identify selective negative regulators of primitive murine AML cells relative to normal bone marrow cells. The top candidate identified was interleukin 4 (IL4), as it showed the most selective inhibition of leukemia cell growth. Stimulating leukemia cells ex vivo with IL4 and transplanting the cells into mice resulted in reduced leukemia burden and prolonged survival compared with controls. In contrast, IL4 did not inhibit the function of normal hematopoietic stem and progenitor cells in long-term bone marrow repopulation assays. Moreover, we found that IL4 treatment of leukemia cells induced Stat6 phosphorylation, and that leukemia cells with Stat6 knocked out using CRISPR/Cas9-genetic engineering were partially resistant to IL4 stimulation, revealing Stat6 as a critical mediator of the IL4 effect. To evaluate whether IL4 has in vivo therapeutic efficacy, we expressed IL4 ectopically in leukemia cells in vivo and also injected IL4 into leukemic mice; both strategies resulted in the suppression of the leukemia cell burden and increased survival. Further analysis revealed that IL4 treatment induces apoptosis in the leukemia cells. Importantly, IL4 exposure also inhibited the growth and survival of primary AML patient cells. In summary, these findings demonstrate that IL4 selectively inhibits AML cells in a Stat6-dependent manner, thus revealing IL4 as a candidate therapeutic agent in AML. IL4 (ProSpec, East Brunswick NJ, USA) was resuspended following the provider guidelines and stored in aliquotes at -80 °C. Mouse MLL-AF9 leukemia cells were provided by Dr. Benjamin Ebert (Brigham and Women’s Hospital, Boston MA, USA). The murine leukemia cells were cultured in SFEM (StemCell Tech) supplemented with 1% penicillin/streptomycin at 37 °C with 5% CO2. Overall design: Mouse MLL-AF9 leukemia cells were grown in 20 ng/mL IL3 with or without IL4 (100 ng/mL) for 18 hours.
Publication Title
Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The 8p11 myeloproliferative syndrome (EMS), also referred to as the stem cell leukemia/lymphoma syndrome, is a chronic myeloproliferative disorder that rapidly progresses into an acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinase activity within FGFR1. The two most common fusion genes in human EMS are ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) and BCR/FGFR1. To study the transcriptional programs becoming deregulated by the FGFR1 fusion genes, global gene expression analysis on human CD34+ cord blood cells expressing either of the fusion oncogenes ZMYM2/FGFR1 and BCR/FGFR1 was performed. As a reference gene we also included the more studied BCR/ABL1 fusion oncogene associated with chronic myeloid leukemia. We found that the 3 different fusion oncogenes had in common the upregulation of several genes involved in the JAK/STAT signalling pathway and also other sets of genes. However, the gene expression profiles were not identical, suggesting that both the tyrosine kinase containing gene and the partner gene would affect the transcription of downstream target genes.
Publication Title
Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 31 Downloadable Samples
- NextSeq 500
Description
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia. Overall design: mRNA sequencing of various immunophenotypic populations from KMT2A-MLLT3 xenograft leukemias with or without FLT3-N676K generated using Illumina NextSeq 500.
Publication Title
FLT3<sup>N676K</sup> drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 40 Downloadable Samples
- NextSeq 500
Description
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Subclonal FLT3N676K mutations also accelerate disease, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 leukemia cells and favored clonal expansion. During clonal evolution, serial genetic changes at the KrasG12D locus was observed, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforced Myc- and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlights the importance of activated signaling as a contributing driver in this disease. Overall design: mRNA sequencing of KMT2A-MLLT3 leukemias with or without activating mutations generated using Illumina NextSeq 500.
Publication Title
De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.
Publication Title
In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling.
Sample Metadata Fields
Cell line, Treatment, Time
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 96 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
The aim of the dataset was to study the effect of music exposure on human blood transcriptome.
Publication Title
The effect of listening to music on human transcriptome.
Sample Metadata Fields
Specimen part, Treatment, Race
View Samples- Saccharomyces cerevisiae
- 28 Downloadable Samples
- Illumina HiSeq 2000
Description
The use of alternative polyadenylation sites is common and affects the post-transcriptional fate of mRNA, including its stability, localization, and translation. Here we present a method for genome-wide and strand-specific mapping of poly(A) sites and quantification of RNA levels at unprecedented efficiency by using an on-cluster dark T-fill procedure on the Illumina sequencing platform. Our method outperforms former protocols in quality and throughput, and reveals new insights into polyadenylation in Saccharomyces cerevisiae. Overall design: Experimental benchmark of five different protocols (3tfill, bpmI, internal, rnaseq and yoon) for genome-wide identification of polyadenylation sites in Saccharomyces cerevisiae and transcript quantification. RNA was extracted from WT cells grown in glucose (ypd) or galactose (ypgal) as carbon source. The same RNA was used for 3 independent library constructions (technical replicates, rep).
Publication Title
An efficient method for genome-wide polyadenylation site mapping and RNA quantification.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We sought to identify the carcinogenic mechanisms involved in RKO cell line with no evidence of activated -catenin/TCF regulated transcription, by comparison its gene expression profile to that of group of colorectal cancer cell lines selected to be mismatch repair
Publication Title
The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
Sequencing of 5' and 3'ends and RNA-seq of PROMPT and mRNA molecules from control and exosome-depleted cells. Overall design: CAGE, 3'TAG and RNAseq library construction from RNA extracted from control and exosome-depleted cells.
Publication Title
Principles for RNA metabolism and alternative transcription initiation within closely spaced promoters.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples