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| Status |
Public on Dec 16, 2010 |
| Title |
Genetic variegation of clonal architecture and stem cells in leukaemia |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
SNP genotyping by SNP array
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| Summary |
Little is known of the genetic architecture of cancer at the subclonal and single cell level or in the stem-like cells responsible for cancer clone maintenance and propagation. We have examined this issue in ALL in which ETV6-RUNX1 gene fuson is an early or initiating genetic lesion followed by a modest number of driver copy number alterations. By multiplexing FISH probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of sub-clones identified and a composite picture of sub-clonal architecture and putative ancestral trees assembled. Sub-clones in ALL have variegated genetics and complex, non-linear or branching evolutionary histories. CNA are independently and recurrently acquired in sub-clones of individual patients, and in no preferential order. Clonal architecture is dynamic and changes in the lead up to a diagnosis and in relapse. Leukaemic stem cells, assayed by transplantation in NOD/SCID IL2Rgamma deficient mice, are also genetically variegated, mirroring sub-clonal patterns. These findings have significant implications for the cancer stem cell concept, for interpretation of cancer genome data and for therapeutic targetting in cancer.
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| Overall design |
Mononuclear cells were isolated at diagnosis of ALL for patient #3 and #7. Transplantation of 2 000 - 2 000 000 unsorted leukaemia cells was performed by intra-tibial injection into 7 - 14 week old NOD/SCID IL2Rgamma deficient mice. Mice were sacrificed when peripheral blood engraftment was >2%. An equivalent of 2 000 - 200 000 CD45 cells were used for serial transplantation. DNA was extracted from mononuclear cells at initial diagnosis and after second transplantation.
Copy number analysis of Affymetrix 500K SNP arrays was performed in CNAG 3.0 for patients #3 and #7 at initial diagnosis and after second transplantation. Reference files were 9 samples from leukemia in remission.
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| Contributor(s) |
Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M |
| Citation(s) |
21160474 |
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| Submission date |
Sep 28, 2010 |
| Last update date |
May 17, 2017 |
| Contact name |
Frederik van Delft |
| Organization name |
ICR
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| Department |
Haemato-oncology
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| Street address |
15 Cotswold Road
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| City |
Belmont |
| ZIP/Postal code |
SM2 5NG |
| Country |
United Kingdom |
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| Platforms (2) |
| GPL3718 |
[Mapping250K_Nsp] Affymetrix Mapping 250K Nsp SNP Array |
| GPL3720 |
[Mapping250K_Sty] Affymetrix Mapping 250K Sty2 SNP Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA132711 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE24412_RAW.tar |
249.2 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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