title: Integrative analysis of RUNX1 downstream pathways and target genes.
abstract: BACKGROUND
  The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia.
  
  
  RESULTS
  Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFbeta, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFbeta. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes.
  
  
  CONCLUSIONS
  This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia. Joelle.Michaud@unil.ch
authors.forename: Joëlle
authors.initials: J
authors.lastname: Michaud
authors.forename: Ken M
authors.initials: KM
authors.lastname: Simpson
authors.forename: Robert
authors.initials: R
authors.lastname: Escher
authors.forename: Karine
authors.initials: K
authors.lastname: Buchet-Poyau
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Catherine
authors.initials: C
authors.lastname: Carmichael
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Ritchie
authors.forename: Frédéric
authors.initials: F
authors.lastname: Schütz
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.forename: Marjorie
authors.initials: M
authors.lastname: Liu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Shen
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.forename: David R
authors.initials: DR
authors.lastname: Turner
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
mesh_terms: D000818:Animals; D001791:Blood Platelet Disorders / Q000235:genetics; D002461:Cell Line, Transformed; D019295:Computational Biology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D050658:Core Binding Factor beta Subunit / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation
chemical_list: C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse