<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis"^^ . "Hematopoietic stem cells (HSCs), positioned at the apex of the hematopoietic lineage, have long been considered a homogeneous population characterized by multipotency and self-renewal. Recent breakthroughs, however, have unveiled profound functional and molecular heterogeneity within this seemingly uniform group. Research from our group has identified a stable and heritable diversity in the intrinsic expression levels of interferon- stimulated genes (ISGs) in HSCs, termed intrinsic IFN signaling heterogeneity. Yet, it remains unclear whether this heterogeneity is established and sustained at the HSC level, and its potential role in the development and progression of clonal hematopoietic malignancies remains unexplored.\r\nIn my thesis, I explore the intrinsic IFN signaling signature in tissue-resident macrophages (TRMs) (aim 1). Utilizing flow cytometry and gene expression analysis, I demonstrated the presence of IFN signaling heterogeneity in TRMs. Importantly, as TRMs originate embryonically and precede HSC development, this finding suggests that IFN signaling heterogeneity in the hematopoietic system is established before the emergence of HSCs.\r\nTo assess the impact of intrinsic IFN signaling heterogeneity in disease (aim 2), I developed a humanized chronic myeloid leukemia (CML) mouse model on the background of a unique ISRE-eGFP reporter mouse. This reporter mouse features the interferon-stimulated response element (ISRE) upstream of eGFP, which enables the identification of HSCs expressing low or high levels of ISGs. In this context, the CML-ISG reporter mouse model facilitated the study of clonal expansion of CML leukemia stem cells (LSCs) relative to the intrinsic IFN signaling status of the parent HSC clone in vivo. Total BM transplantation experiments revealed a significant expansion of eGFPlow leukemic clones in the peripheral blood, together with a quiescent eGFPlow LSC pool in the BM suggesting a more aggressive leukemia clone. Survival analysis revealed that 100% eGFPlow leukemic chimeras succumbed to leukemia significantly faster that eGFPhigh chimeras confirming my findings.\r\nAdditionally, I established a reliable method for isolating exosome-enriched small extracellular vesicles (sEVs) through serial centrifugation followed by size exclusion chromatography (SEC) (aim 3) in order to explore the role of sEV signaling in the BM (aim 4). My findings indicated a shift in sEV profile and content upon inflammatory stress, with specific sorting of inflammatory response proteins into vesicles exhibiting an inhibitory effect on hematopoietic stem and progenitor cells (HSPCs) proliferation in vitro. Subsequent in vivo experiments I performed using different mouse models demonstrated a dynamic release of sEVs in response to acute inflammatory stress, suggesting the hematopoietic compartment as a major source of sEVs during such conditions.\r\nIn summary, my research has provided new insight on the origins of intrinsic IFN signaling heterogeneity and its consequential influence on disease progression in CML. Furthermore, it advanced our understanding of the intricate role played by sEV signaling in modulating the acute inflammatory response within the BM."^^ . "2024" . . . . . . . "Abdul Rahman"^^ . "itani"^^ . "Abdul Rahman itani"^^ . . . . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (PDF)"^^ . . . "thesis 2024-4-02.pdf"^^ . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Stress Signaling Heterogeneity in Normal and\r\nMalignant Hematopoiesis (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #34654 \n\nStress Signaling Heterogeneity in Normal and \nMalignant Hematopoiesis\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .