title: Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target.
abstract: 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.
authors: Centre de recherche en infectiologie du CHUL, Centre de recherche du CHU de Québec, Quebec City, Quebec, Canada.|CHU de Québec Hôpital Enfant-Jésus, Quebec City, Quebec, Canada.|Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
authors: F
authors: F
authors: Barabé
authors: Centre de recherche en infectiologie du CHUL, Centre de recherche du CHU de Québec, Quebec City, Quebec, Canada.
authors: L
authors: L
authors: Gil
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: M
authors: M
authors: Celton
authors: Centre de recherche en infectiologie du CHUL, Centre de recherche du CHU de Québec, Quebec City, Quebec, Canada.
authors: A
authors: A
authors: Bergeron
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: V
authors: V
authors: Lamontagne
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: É
authors: É
authors: Roques
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: K
authors: K
authors: Lagacé
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: A
authors: A
authors: Forest
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: R
authors: R
authors: Johnson
authors: Department of Pediatrics, Division of Hematology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: L
authors: L
authors: Pécheux
authors: Centre de recherche en infectiologie du CHUL, Centre de recherche du CHU de Québec, Quebec City, Quebec, Canada.
authors: J
authors: J
authors: Simard
authors: Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Laboratory for Cancer Immunobiology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada.
authors: J
authors: J
authors: Pelloux
authors: Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Laboratory for Cancer Immunobiology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada.
authors: A
authors: A
authors: Bellemare-Pelletier
authors: Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Laboratory for Cancer Immunobiology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada.|Department of Microbiology and Immunology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada.
authors: E
authors: E
authors: Gagnon
authors: Division of Hematology-Oncology and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada.|Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors: J
authors: J
authors: Hébert
authors: Department of Pediatrics, Division of Hematology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.
authors: S
authors: S
authors: Cellot
authors: Laboratory for High throughput biology, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Ste-Justine Hospital, Université de Montréal, Montréal, Quebec, Canada.|Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors: B T
authors: BT
authors: Wilhelm
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D014162:Transfection
chemical_list: D015415:Biomarkers; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human