PloS one, 2012-12, Vol.7 (12), p.e51228
2012
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- Autor(en) / Beteiligte
- Titel
- Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice
- Ist Teil von
- PloS one, 2012-12, Vol.7 (12), p.e51228
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0051228Titel-ID: cdi_plos_journals_1339507333
- Format
- –
- Schlagworte
- Acute myeloid leukemia, Analysis, Animal tissues, Animals, Apoptosis, B cells, Biology, Biopsy, Bone marrow, Bone morphogenetic proteins, Cancer, Cell division, Cell survival, Chronic myelomonocytic leukemia, Clonal deletion, Cytokines, Cytokines - physiology, Disease, Epithelial cells, Flow Cytometry, Gene Deletion, Genetic transformation, Genomic instability, Hematopoietic stem cells, Hepatocytes, Immunology, In Situ Hybridization, Fluorescence, Infiltration, Intestine, Karyotyping, Keratinocytes, Kinases, Leukemia, Leukemia, Myelomonocytic, Acute - genetics, Leukemogenesis, Ligands, Lymphocytes, Lymphocytes B, Lymphocytes T, MAP Kinase Kinase Kinases - genetics, Medicine, Mice, Mice, Knockout, Myeloid leukemia, Myelomonocytic leukemia, NF-κB protein, Phosphorylation, Prostate, Rodents, Signal Transduction, Splenomegaly, Splenomegaly - genetics, Stability, Stem cell transplantation, Stem cells, Survival, T cells, TAK1 protein, Transformation, Transforming growth factors, Tumor necrosis factor receptors, Tumor necrosis factor-TNF, Tumorigenesis