Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice
| Autor: | Yun-Ju Lai, Zeev Estrov, Min Xie, Michael Ho, Jing Wang, Cynthia R. Lockworth, Alejandro D. Campos, Lana Hur, Chen Dong, Sity Dawud, Bryant G. Darnay, Carlos E. Bueso-Ramos, Diep Tran, Hui Kuan Lin, Natalia Martin Orozco, Peter Hu, Jared Jakacky, Michael D. Schneider, Betty Lamothe |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Myeloid
Mouse NF-KAPPA-B lcsh:Medicine CHROMOSOMAL INSTABILITY Hematologic Cancers and Related Disorders Mice 0302 clinical medicine hemic and lymphatic diseases Molecular Cell Biology lcsh:Science PHOSPHORYLATION In Situ Hybridization Fluorescence Mice Knockout 0303 health sciences Multidisciplinary Kinase Myeloid leukemia Animal Models Signaling in Selected Disciplines Flow Cytometry MAP Kinase Kinase Kinases CANCER 3. Good health APOPTOSIS Multidisciplinary Sciences Haematopoiesis Leukemia medicine.anatomical_structure DIFFERENTIATION Oncology IKK-BETA 030220 oncology & carcinogenesis Medicine Science & Technology - Other Topics Cytokines Cellular Types Stem cell REGULATOR Research Article Signal Transduction Acute Myeloid Leukemia General Science & Technology Chronic myelomonocytic leukemia Bone Marrow Cells Biology Leukemia Myelomonocytic Acute SIGNALING PATHWAYS 03 medical and health sciences Model Organisms Leukemias medicine Animals 030304 developmental biology Oncogenic Signaling Science & Technology MAP kinase kinase kinase lcsh:R Cancers and Neoplasms medicine.disease Karyotyping Immunology Splenomegaly Cancer research KINASE ACTIVATION lcsh:Q Gene Deletion |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 12, p e51228 (2012) |
| Popis: | Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis. |
| Databáze: | OpenAIRE |
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