Coordinated BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. Persistence of oncogenic p27 functions despite effective inhibition of BCR-ABL1 may contribute to resistance to tyrosine kinase inhibitors. Overall design: BCR-ABL1 induced p27 versus knockout, controlling with Empty vector p27 versus knock out
BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.
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View SamplesMicroarray data of mouse primary E2A-PBX1 leukemias and preleukemia cells were compared to wild-type B-cell progenitor cells
E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia.
Sex, Specimen part
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Epigenetic roles of MLL oncoproteins are dependent on NF-κB.
Specimen part, Cell line
View SamplesChromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene occur in primary and treatment-related leukemias, and confer a poor prognosis. Studies based primarily on mouse models have substantially advanced our understanding of MLL leukemia pathogenesis, but often employ supra-physiologic oncogene expression with uncertain implications for human leukemia. Genome editing using site-specific nucleases provides a powerful new technology for gene modification to potentially model human disease, however this approach has not been used to recreate acute leukemia in human cells of origin comparable to disease observed in patients. We applied TALEN-mediated genome editing to generate endogenous MLL-AF9 and MLL-ENL oncogenes through insertional mutagenesis in primary human hematopoietic stem and progenitor cells (HSPCs) derived from human umbilical cord blood. Engineered HSPCs displayed altered in vitro growth potentials and induced acute leukemias following transplantation in immuno-compromised mice at a mean latency of 14.5 weeks. The leukemias displayed phenotypic and morphologic similarities with patient leukemia blasts including a subset with mixed phenotype, a distinctive feature seen in clinical disease. The leukemic blasts expressed an MLL-associated transcriptional program with elevated levels of crucial MLL target genes, displayed heightened sensitivity to DOT1L inhibition, and demonstrated increased oncogenic potential ex vivo and in secondary transplant assays. Thus, genome editing to create endogenous MLL oncogenes in primary human HSPCs faithfully models acute MLL-rearranged leukemia and provides an experimental platform for prospective studies of leukemia initiation and stem cell biology in a genetic subtype of poor prognosis leukemia.
MLL leukemia induction by genome editing of human CD34+ hematopoietic cells.
Specimen part
View SamplesAdjuvants are critical for the success of vaccines, and agonists for microbial pattern recognition receptors are promising new candidates. A mechanism for the immune enhancing role of adjuvants is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double stranded RNA (poly ICLC), a ligand for TLR3 and MDA-5 cytosolic RNA helicase. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC showed upregulation of genes involved in multiple innate immune pathways in all subjects, including interferon and inflammasome signaling. Blocking of type I interferon receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate pathways were similarly induced in volunteers immunized with the highly efficacious Yellow Fever Vaccine. Therefore a chemically defined microbial agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immunity, here for a live attenuated viral vaccine in humans.
Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans.
Time
View SamplesRNA sequencing of PLZF+ and PLZF- ?d T cell subsets from adipose tissue for gene expression analysis Overall design: PLZF+ and PLZF- ?d T cells were sorted from adipose tissue of PLZF-GFP mice for subsequent RNA sequencing and gene-expression analysis. Two replicates for each subset pooled from 10 mice each were used for the study.
γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.
Sex, Specimen part, Cell line, Subject
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EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Specimen part, Cell line, Treatment
View SamplesWe studied transcriptional changes by Affymetrix human microarrays in DLBCL cell lines as a result of treatment with GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Specimen part, Cell line, Treatment
View SamplesWe studied transcriptional changes by Affymetrix human microarrays in 2 DLBCL cell lines as a result of shRNA mediated knockdown of EZH2.
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Specimen part, Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.
Specimen part, Cell line
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