Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3519594?pdf=render |
| _version_ | 1817982862382596096 |
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| author | Betty Lamothe Yunju Lai Lana Hur Natalia Martin Orozco Jing Wang Alejandro D Campos Min Xie Michael D Schneider Cynthia R Lockworth Jared Jakacky Diep Tran Michael Ho Sity Dawud Chen Dong Hui-Kuan Lin Peter Hu Zeev Estrov Carlos E Bueso-Ramos Bryant G Darnay |
| author_facet | Betty Lamothe Yunju Lai Lana Hur Natalia Martin Orozco Jing Wang Alejandro D Campos Min Xie Michael D Schneider Cynthia R Lockworth Jared Jakacky Diep Tran Michael Ho Sity Dawud Chen Dong Hui-Kuan Lin Peter Hu Zeev Estrov Carlos E Bueso-Ramos Bryant G Darnay |
| author_sort | Betty Lamothe |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T23:25:44Z |
| format | Article |
| id | doaj.art-f98ab889e1f742eb83b60ac8a1485b44 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T23:25:44Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f98ab889e1f742eb83b60ac8a1485b442022-12-22T02:25:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5122810.1371/journal.pone.0051228Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice.Betty LamotheYunju LaiLana HurNatalia Martin OrozcoJing WangAlejandro D CamposMin XieMichael D SchneiderCynthia R LockworthJared JakackyDiep TranMichael HoSity DawudChen DongHui-Kuan LinPeter HuZeev EstrovCarlos E Bueso-RamosBryant G DarnayPrevious 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.http://europepmc.org/articles/PMC3519594?pdf=render |
| spellingShingle | Betty Lamothe Yunju Lai Lana Hur Natalia Martin Orozco Jing Wang Alejandro D Campos Min Xie Michael D Schneider Cynthia R Lockworth Jared Jakacky Diep Tran Michael Ho Sity Dawud Chen Dong Hui-Kuan Lin Peter Hu Zeev Estrov Carlos E Bueso-Ramos Bryant G Darnay Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. PLoS ONE |
| title | Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. |
| title_full | Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. |
| title_fullStr | Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. |
| title_full_unstemmed | Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. |
| title_short | Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice. |
| title_sort | deletion of tak1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice |
| url | http://europepmc.org/articles/PMC3519594?pdf=render |
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