title: Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias.
abstract: High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia.
authors.affiliation: 1] Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia [2] Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Tursky
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Beck
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: J A I
authors.initials: JA
authors.lastname: Thoms
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Knezevic
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Richards
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynaecology, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Morris
authors.affiliation: 1] Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Goldberg
authors.affiliation: 1] Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Izraeli
authors.affiliation: Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: J W H
authors.initials: JW
authors.lastname: Wong
authors.affiliation: School of Mathematics and Statistics, UNSW, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Olivier
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: R B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: MacKenzie
authors.affiliation: 1] Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia [2] Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Pimanda
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG