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| Status |
Public on Jan 09, 2013 |
| Title |
Cell of origin determines clinically relevant subtypes of MLL-rearranged AML |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.
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| Overall design |
Differential DNA methylation between of LSC isolated from murine HSC and GMP derived AMLs
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| Contributor(s) |
Krivstov A, Armstrong S, Figueroa ME, Melnick A |
| Citation(s) |
23235717 |
| Submission date |
Jan 08, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Maria Eugenia Figueroa |
| E-mail(s) |
mef162@miami.edu
|
| Organization name |
University of Miiami
|
| Department |
Human Genetics
|
| Lab |
Maria Figueroa
|
| Street address |
1501 NW 10th Ave, BRB 709A, Locator code C227
|
| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (7)
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| Relations |
| BioProject |
PRJNA185474 |
| SRA |
SRP017807 |
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