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

Szczegóły
Abstrakt

Tytuł:: Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia.
Autorzy:: Goldberg L; Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel;
Tijssen MR
Birger Y
Hannah RL
Kinston SJ
Schütte J
Beck D
Knezevic K
Schiby G
Jacob-Hirsch J
Biran A
Kloog Y
Marcucci G
Bloomfield CD
Aplan PD
Pimanda JE
Göttgens B
Izraeli S
Źródło:: Blood [Blood] 2013 Oct 10; Vol. 122 (15), pp. 2694-703. Date of Electronic Publication: 2013 Aug 23.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
MeSH Terms:: Gene Expression Regulation, Leukemic/*physiology
Leukemia, Myeloid, Acute/*genetics
Proto-Oncogene Proteins c-pim-1/*metabolism
Trans-Activators/*genetics
Transcription Factors/*metabolism
Animals ; Antineoplastic Agents ; Enhancer Elements, Genetic/genetics ; Genomics ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Myeloid Progenitor Cells/physiology ; Neoplasm Transplantation ; Transcription, Genetic/physiology ; Transcriptional Regulator ERG
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Grant Information:: P50 CA140158 United States CA NCI NIH HHS; MC_PC_12009 United Kingdom MRC_ Medical Research Council; 079249 United Kingdom Wellcome Trust; G0900729/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; 12765 United Kingdom CRUK_ Cancer Research UK; United Kingdom Wellcome Trust; NCI P50 CA 140158 United States CA NCI NIH HHS; 100140 United Kingdom Wellcome Trust
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (ERG protein, human)
0 (Trans-Activators)
0 (Transcription Factors)
0 (Transcriptional Regulator ERG)
EC 2.7.11.1 (PIM1 protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
Entry Date(s):: Date Created: 20130827 Date Completed: 20131204 Latest Revision: 20220129
Update Code:: 20240104
PubMed Central ID:: PMC3795462
DOI:: 10.1182/blood-2013-01-477133
PMID:: 23974202
: Czasopismo naukowe

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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