title: Systematic computation with functional gene-sets among leukemic and hematopoietic stem cells reveals a favorable prognostic signature for acute myeloid leukemia.
abstract: BACKGROUND
  Genes that regulate stem cell function are suspected to exert adverse effects on prognosis in malignancy. However, diverse cancer stem cell signatures are difficult for physicians to interpret and apply clinically. To connect the transcriptome and stem cell biology, with potential clinical applications, we propose a novel computational "gene-to-function, snapshot-to-dynamics, and biology-to-clinic" framework to uncover core functional gene-sets signatures. This framework incorporates three function-centric gene-set analysis strategies: a meta-analysis of both microarray and RNA-seq data, novel dynamic network mechanism (DNM) identification, and a personalized prognostic indicator analysis. This work uses complex disease acute myeloid leukemia (AML) as a research platform.
  
  
  RESULTS
  We introduced an adjustable "soft threshold" to a functional gene-set algorithm and found that two different analysis methods identified distinct gene-set signatures from the same samples. We identified a 30-gene cluster that characterizes leukemic stem cell (LSC)-depleted cells and a 25-gene cluster that characterizes LSC-enriched cells in parallel; both mark favorable-prognosis in AML. Genes within each signature significantly share common biological processes and/or molecular functions (empirical p = 6e-5 and 0.03 respectively). The 25-gene signature reflects the abnormal development of stem cells in AML, such as AURKA over-expression. We subsequently determined that the clinical relevance of both signatures is independent of known clinical risk classifications in 214 patients with cytogenetically normal AML. We successfully validated the prognosis of both signatures in two independent cohorts of 91 and 242 patients respectively (log-rank p < 0.0015 and 0.05; empirical p < 0.015 and 0.08).
  
  
  CONCLUSIONS
  The proposed algorithms and computational framework will harness systems biology research because they efficiently translate gene-sets (rather than single genes) into biological discoveries about AML and other complex diseases.
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. xyang2@uchicago.edu.
authors.forename: Xinan Holly
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. limeiyi@sibs.ac.cn.
authors.forename: Meiyi
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. bwang@peds.bsd.uchicago.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Laboratory Schools, The University of Chicago, Chicago, USA. 1213.ghs@gmail.com.
authors.forename: Wanqi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. adesgard@bsd.uchicago.edu.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Desgardin
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. konel@peds.bsd.uchicago.edu.
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. jdejong@peds.bsd.uchicago.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, USA. jchen@medicine.bsd.uchicago.edu.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. lnchen@sibs.ac.cn.
authors.forename: Luonan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, and Comer Children's Hospital, Section of Hematology/Oncology, The University of Chicago, 900 East 57th Street, KCBD Room 5121, Chicago, Illinois, 60637, USA. jmcunningham@uchicago.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Cunningham
mesh_terms: D000465:Algorithms; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D059467:Transcriptome