Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target
Autor: | É Roques, Julie Pelloux, L Pécheux, Audrey Forest, J Simard, Magalie Celton, Josée Hébert, Etienne Gagnon, Radia M. Johnson, Brian T. Wilhelm, L Gil, Vikie Lamontagne, Sonia Cellot, Anne Bergeron, Angelique Bellemare-Pelletier, Frédéric Barabé, Karine Lagacé |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Myeloid Oncogene Proteins Fusion Transfection Models Biological Receptor tyrosine kinase Cell Line Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Progenitor cell neoplasms Cell Proliferation biology Genetic heterogeneity Proto-Oncogene Proteins c-ret Myeloid leukemia Hematology medicine.disease Clone Cells Leukemia Myeloid Acute Haematopoiesis Leukemia 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology biology.protein Cancer research Stem cell Biomarkers Myeloid-Lymphoid Leukemia Protein |
Zdroj: | Leukemia. 31:1166-1176 |
ISSN: | 1476-5551 0887-6924 |
Popis: | 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 AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required. We identify 39 biomarkers whose high expression level is specific to this genetic subtype of AML and validate that many of these have diagnostic utility. We further examined one biomarker, the receptor tyrosine kinase (RTK) RET, and show through shRNA knockdowns that its expression is essential for in vivo and in vitro growth of MA9-AML. These results highlight the value of novel human models of AML derived from single donors using specific oncogenic fusions to understand their biology and to uncover potential therapeutic targets. |
Databáze: | OpenAIRE |
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