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dc.contributor.advisorPietras, Eric
dc.contributor.authorRabe, Jennifer
dc.contributor.committeememberPietras, Eric
dc.contributor.committeememberFord, Heide
dc.contributor.committeememberDeGregori, James
dc.contributor.committeememberErnst, Patricia
dc.contributor.committeememberSlansky, Jill
dc.date.accessioned2020-01-14T15:44:26Z
dc.date.available2022-01-06T15:44:31Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractChronic inflammation, often driven by the pro-inflammatory cytokine IL-1, is commonly found in patients with auto-immune disorders, hematological malignancies, or obesity, as well as in aging individuals. Hematopoietic stem cells (HSCs) exposed to chronic inflammatory stimuli exhibit altered HSC potential and decreased long-term repopulating activity. However, secondary transplant of these HSCs does not result in bone marrow failure, suggesting that some HSCs are able to prevent exhaustion in the face of chronic inflammation. To understand why, we used an IL-1 driven mouse model of chronic inflammation to identify the transcription factor PU.1 as a mediator of a return to quiescence in long term HSCs. This work reveals a new role for PU.1 in the HSC response to long-term inflammation, one which returns HSCs to their normally quiescent state. Impairment of this PU.1 mechanism may predispose cells for the development of malignancy. Evasion of the immune system is an important step in cancer development. However, the mechanisms of immune evasion during leukemia progression remain poorly understood. Using a mouse model of acute lymphoblastic leukemia (ALL), we investigated the role of calcineurin (Cn) in ALL progression and observed that knocking-down Cn in leukemia cells dramatically prolonged survival in immune-competent but not immune-deficient recipients, suggesting a role for Cn in leukemia cell immune evasion. We identified T cells as the primary immune cells eliminating the Cn-deficient leukemia and found increased secretion of IL-12, a T cell activating cytokine, from the leukemia cells with reduced Cn. Strikingly, administering recombinant IL-12 prolonged survival of mice challenged with the highly aggressive Cn competent ALL. These data suggest that leukemia cells are dependent upon Cn for immune evasion by restricting the regulation of pro-inflammatory genes, particularly IL-12.
dc.identifierRabe_ucdenveramc_1639D_10674.pdf
dc.identifier.urihttps://hdl.handle.net/10968/4761
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 01/06/2022
dc.subject.meshHematopoiesis
dc.subject.meshCalcineurin
dc.subject.meshLeukemia
dc.subject.meshInterleukin-12
dc.subject.meshInterleukin-1
dc.titleInflammatory cytokines as critical regulators of hematopoiesis and leukemia progression
dc.typeThesis
dcterms.embargo.expires2022-01-06
thesis.degree.disciplineMolecular Biology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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