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Integrated analysis of MLL-AF9 AML patients and model leukemias highlights RET and other novel therapeutic targets [RNA-Seq_normal]

ABSTRACT: Next generation DNA sequencing of acute myeloid leukemia (AML) patient samples has revealed novel recurrent mutations while at the same time highlighting the genetic heterogeneity of the disease. These observations suggest that an extraordinarily large number of combinations of mutations can contribute to leukemogenesis. In order to address the question of the contribution of patient genetic background to AML we have developed a model system to generate multiple human leukemias in a single donor’s genetic background. Stepwise RNA-seq data from this model shows that in the context of AML driven by the MLL-AF9 (MA9) oncogene, the genetic background of the donor does not have a detectable effect. Comparison of these model leukemias from multiple single donors to AML patient samples containing MA9 translocations revealed conserved gene expression patterns not previously highlighted in this genetic sub-type. We further demonstrate that the expression of one of these genes, RET, is essential both in vivo and in vitro growth of MA9 AMLs . Transcriptome of normal cells (CD34+) from different donors

ORGANISM(S): Homo sapiens  

SUBMITTER: Magalie Celton  

PROVIDER: E-GEOD-71689 | ArrayExpress | 2017-05-02



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Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target.

Barabé F F   Gil L L   Celton M M   Bergeron A A   Lamontagne V V   Roques É É   Lagacé K K   Forest A A   Johnson R R   Pécheux L L   Simard J J   Pelloux J J   Bellemare-Pelletier A A   Gagnon E E   Hébert J J   Cellot S S   Wilhelm B T BT  

Leukemia 20161026 5

Acute myeloid leukemias (AMLs) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell that gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and  ...[more]

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