Journal
BLOOD
Volume 122, Issue 15, Pages 2694-2703Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-01-477133
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Funding
- Israel Science Foundation
- Israel Centers of Research Excellence [41/11]
- Children with Cancer UK
- Waxman Foundation
- Israel Cancer Research Foundation
- Academy of Medical Sciences
- The European Hematology Association
- Marie Curie Intra-European Fellowship [237296]
- Leukaemia and Lymphoma Research Studentship
- Leukaemia and Lymphoma Research and Cancer Research UK
- Wellcome Trust
- Wellcome Trust-MRC Cambridge Stem Cell Institute
- NCI [P50 CA 140158]
- The Coleman Leukemia Research Foundation
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- Cancer Research UK [12765] Funding Source: researchfish
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
- BBSRC [BB/I00050X/1] Funding Source: UKRI
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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.
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