23 research outputs found
Ancient Latin American objects in the archive: selections from the George and Louise Patten collection of Salem Hyde cultural artifacts at the University of Tennessee at Chattanooga
https://scholar.utc.edu/exhibition-records/1004/thumbnail.jp
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Interleukin-10 Deficiency Drives the Development of Mouse B cell Leukemia/Lymphoma
Excessive inflammatory responses to common childhood infections are associated with an increased risk of pediatric B cell Acute Lymphoblastic Leukemia (B ALL). Despite the identification of several neonatal inflammatory markers as B ALL risk factors, the mechanism(s) by which these markers stimulate an excessive immune response leading B ALL remain largely unknown. Here, we demonstrate that IL 10 deficiency, a neonatal risk factor for B ALL, indirectly impairs B lymphopoiesis and increases B cell DNA damage through induction of inflammation in mice. Altered B cell number and DNA damage in Il10-/- mice were associated with a module of 6 pro inflammatory/myeloid associated cytokines (IL-1, IL-6, IL-12p40, IL 13, CCL4/MIP 1, and G CSF). Importantly, inflammation and defects in bone marrow B cells were attenuated by treating pre leukemic Il10-/- Ckdn2a-/- mice with antibiotics that target Helicobacter species. In the TEL AML1 Ckdn2a-/- mouse model of B ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of B cell neoplasm to favor C>T and T>C mutations. Infection of Cdkn2a-/- mice to Aspiculuris, a parasite that induces IL-10 production, delayed the development of B cell neoplasms in Cdkn2a / mice, demonstrating a novel protective effect of microbial exposure. Our results identify commensal bacteria as modulators of bone marrow B cell responses to IL 10 deficiency, and suggest that microbial dysbiosis underlies the infectious etiology of pediatric B ALL
Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia
Mechanism of IL-10 Protective Effect in Development of Childhood B Cell Acute Lymphoblastic Leukemia
Resistance to mTOR Kinase Inhibitors in Lymphoma Cells Lacking 4EBP1
<div><p>Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive “active-site” mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.</p></div
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Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia.
Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia