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Integrative analysis of RUNX1 downstream pathways and target genes

Show simple item record Michaud, Joelle en_US Simpson, Ken M. en_US Escher, Robert en_US Buchet-Poyau, Karine en_US Beissbarth, Tim en_US Carmichael, Catherine en_US Ritchie, Matthew E. en_US Schutz, Frederic en_US Cannon, Ping en_US Liu, Marjorie en_US Shen, Xiaofeng en_US Ito, Yoshiaki en_US Raskind, Wendy H. en_US Horwitz, Marshall S. en_US Osato, Motomi en_US Turner, David R. en_US Speed, Terence P. en_US Kavallaris, Maria en_US Smyth, Gordon K. en_US Scott, Hamish S. en_US 2010-05-06T20:04:43Z 2010-05-06T20:04:43Z 2008 en_US
dc.identifier.citation Michaud J, Simpson K, Escher R, et al. Integrative analysis of RUNX1 downstream pathways and target genes. BMC Genomics. 2008;9(1):363. en_US
dc.identifier.other 10.1186/1471-2164-9-363 en_US
dc.identifier.uri en_US
dc.description.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 CBF[Beta], 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, CBF[Beta]. 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. Conclusion: 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. en_US
dc.language.iso en_US en_US
dc.title Integrative analysis of RUNX1 downstream pathways and target genes en_US
dc.type Article en_US

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