Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

Liat Goldberg, Marloes R. Tijssen, Yehudit Birger, Rebecca L. Hannah, Sarah J. Kinston, Judith Schütte, Dominik Beck, Kathy Knezevic, Ginette Schiby, Jasmine Jacob-Hirsch, Anat Biran, Yoel Kloog, Guido Marcucci, Clara D. Bloomfield, Peter D. Aplan, John E. Pimanda, Berthold Göttgens, Shai Izraeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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 panhematopoietic ERG expression induces a nearly progenitor myeloid leukemia in trans genic 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.

Original languageEnglish
Pages (from-to)2694-2703
Number of pages10
JournalBlood
Volume122
Issue number15
DOIs
StatePublished - 10 Oct 2013

Funding

FundersFunder number
National Cancer InstituteP50CA140158

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