Oncogenic Kras initiates leukemia in hematopoietic stem cells.
How oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effec...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-03-01
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| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC2656550?pdf=render |
| _version_ | 1818439553394933760 |
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| author | Amit J Sabnis Laurene S Cheung Monique Dail Hio Chung Kang Marianne Santaguida Michelle L Hermiston Emmanuelle Passegué Kevin Shannon Benjamin S Braun |
| author_facet | Amit J Sabnis Laurene S Cheung Monique Dail Hio Chung Kang Marianne Santaguida Michelle L Hermiston Emmanuelle Passegué Kevin Shannon Benjamin S Braun |
| author_sort | Amit J Sabnis |
| collection | DOAJ |
| description | How oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effects of expressing oncogenic Kras(G12D) from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by Kras(G12D) expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. Kras(G12D) HSCs demonstrated a marked in vivo competitive advantage over wild-type cells. Kras(G12D) expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted Kras(G12D) HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. We conclude that MPD-initiating activity is restricted to the HSC compartment in Kras(G12D) mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression. |
| first_indexed | 2024-12-14T17:58:17Z |
| format | Article |
| id | doaj.art-55fb03daa2bc4376b9d210391fe4c84f |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-14T17:58:17Z |
| publishDate | 2009-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-55fb03daa2bc4376b9d210391fe4c84f2022-12-21T22:52:29ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-03-0173e5910.1371/journal.pbio.1000059Oncogenic Kras initiates leukemia in hematopoietic stem cells.Amit J SabnisLaurene S CheungMonique DailHio Chung KangMarianne SantaguidaMichelle L HermistonEmmanuelle PasseguéKevin ShannonBenjamin S BraunHow oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effects of expressing oncogenic Kras(G12D) from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by Kras(G12D) expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. Kras(G12D) HSCs demonstrated a marked in vivo competitive advantage over wild-type cells. Kras(G12D) expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted Kras(G12D) HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. We conclude that MPD-initiating activity is restricted to the HSC compartment in Kras(G12D) mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression.http://europepmc.org/articles/PMC2656550?pdf=render |
| spellingShingle | Amit J Sabnis Laurene S Cheung Monique Dail Hio Chung Kang Marianne Santaguida Michelle L Hermiston Emmanuelle Passegué Kevin Shannon Benjamin S Braun Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biology |
| title | Oncogenic Kras initiates leukemia in hematopoietic stem cells. |
| title_full | Oncogenic Kras initiates leukemia in hematopoietic stem cells. |
| title_fullStr | Oncogenic Kras initiates leukemia in hematopoietic stem cells. |
| title_full_unstemmed | Oncogenic Kras initiates leukemia in hematopoietic stem cells. |
| title_short | Oncogenic Kras initiates leukemia in hematopoietic stem cells. |
| title_sort | oncogenic kras initiates leukemia in hematopoietic stem cells |
| url | http://europepmc.org/articles/PMC2656550?pdf=render |
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