Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities.
The discovery of chromosomal translocations in leukemia/lymphoma and sarcomas presaged a widespread discovery in epithelial tumors. With the advent of new-generation whole-genome sequencing, many consistent chromosomal abnormalities have been described together with putative driver and passenger mut...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research Inc.
2014
|
| _version_ | 1797064219912306688 |
|---|---|
| author | Chambers, J Tanaka, T Brend, T Ali, H Geisler, N Khazin, L Cigudosa, J Dear, T MacLennan, K Rabbitts, T |
| author_facet | Chambers, J Tanaka, T Brend, T Ali, H Geisler, N Khazin, L Cigudosa, J Dear, T MacLennan, K Rabbitts, T |
| author_sort | Chambers, J |
| collection | OXFORD |
| description | The discovery of chromosomal translocations in leukemia/lymphoma and sarcomas presaged a widespread discovery in epithelial tumors. With the advent of new-generation whole-genome sequencing, many consistent chromosomal abnormalities have been described together with putative driver and passenger mutations. The multiple genetic changes required in mouse models to assess the interrelationship of abnormalities and other mutations are severe limitations. Here, we show that sequential gene targeting of embryonic stem cells can be used to yield progenitor cells to generate chimeric offspring carrying all the genetic changes needed for cell-specific cancer. Illustrating the technology, we show that MLL-ENL fusion is sufficient for lethal leukocytosis and proof of genome integrity comes from germline transmission of the sequentially targeted alleles. This accelerated technology leads to a reduction in mouse numbers (contributing significantly to the 3Rs), allows fluorescence tagging of cancer-initiating cells, and provides a flexible platform for interrogating the interaction of chromosomal abnormalities with mutations. |
| first_indexed | 2024-03-06T21:11:08Z |
| format | Journal article |
| id | oxford-uuid:3e308e2b-d135-480b-8122-3d131d8cdc40 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:11:08Z |
| publishDate | 2014 |
| publisher | American Association for Cancer Research Inc. |
| record_format | dspace |
| spelling | oxford-uuid:3e308e2b-d135-480b-8122-3d131d8cdc402022-03-26T14:24:08ZSequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3e308e2b-d135-480b-8122-3d131d8cdc40EnglishSymplectic Elements at OxfordAmerican Association for Cancer Research Inc.2014Chambers, JTanaka, TBrend, TAli, HGeisler, NKhazin, LCigudosa, JDear, TMacLennan, KRabbitts, TThe discovery of chromosomal translocations in leukemia/lymphoma and sarcomas presaged a widespread discovery in epithelial tumors. With the advent of new-generation whole-genome sequencing, many consistent chromosomal abnormalities have been described together with putative driver and passenger mutations. The multiple genetic changes required in mouse models to assess the interrelationship of abnormalities and other mutations are severe limitations. Here, we show that sequential gene targeting of embryonic stem cells can be used to yield progenitor cells to generate chimeric offspring carrying all the genetic changes needed for cell-specific cancer. Illustrating the technology, we show that MLL-ENL fusion is sufficient for lethal leukocytosis and proof of genome integrity comes from germline transmission of the sequentially targeted alleles. This accelerated technology leads to a reduction in mouse numbers (contributing significantly to the 3Rs), allows fluorescence tagging of cancer-initiating cells, and provides a flexible platform for interrogating the interaction of chromosomal abnormalities with mutations. |
| spellingShingle | Chambers, J Tanaka, T Brend, T Ali, H Geisler, N Khazin, L Cigudosa, J Dear, T MacLennan, K Rabbitts, T Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title | Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title_full | Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title_fullStr | Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title_full_unstemmed | Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title_short | Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities. |
| title_sort | sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities |
| work_keys_str_mv | AT chambersj sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT tanakat sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT brendt sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT alih sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT geislern sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT khazinl sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT cigudosaj sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT deart sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT maclennank sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities AT rabbittst sequentialgenetargetingtomakechimerictumormodelswithdenovochromosomalabnormalities |