title: Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia.
abstract: The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34(+) normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias.
authors: Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel;
authors: Liat
authors: L
authors: Goldberg
authors: Marloes R
authors: MR
authors: Tijssen
authors: Yehudit
authors: Y
authors: Birger
authors: Rebecca L
authors: RL
authors: Hannah
authors: Sarah J
authors: SJ
authors: Kinston
authors: Judith
authors: J
authors: Schütte
authors: Dominik
authors: D
authors: Beck
authors: Kathy
authors: K
authors: Knezevic
authors: Ginette
authors: G
authors: Schiby
authors: Jasmine
authors: J
authors: Jacob-Hirsch
authors: Anat
authors: A
authors: Biran
authors: Yoel
authors: Y
authors: Kloog
authors: Guido
authors: G
authors: Marcucci
authors: Clara D
authors: CD
authors: Bloomfield
authors: Peter D
authors: PD
authors: Aplan
authors: John E
authors: JE
authors: Pimanda
authors: Berthold
authors: B
authors: Göttgens
authors: Shai
authors: S
authors: Izraeli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D023281:Genomics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000502:physiology; D009368:Neoplasm Transplantation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D000071230:Transcriptional Regulator ERG
chemical_list: D000970:Antineoplastic Agents; C072312:ERG protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
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