Integrative analysis of RUNX1 downstream pathways and target genes
Files
(Published version)
Date
2008
Authors
Michaud, J.
Simpson, K.
Escher, R.
Buchet-Poyau, K.
Beissbarth, T.
Carmichael, C.
Ritchie, M.
Schutz, F.
Cannon, P.
Liu, M.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
BMC Genomics, 2008; 9(1):1-17
Statement of Responsibility
Joëlle Michaud, Ken M Simpson, Robert Escher, Karine Buchet-Poyau, Tim Beissbarth, Catherine Carmichael, Matthew E Ritchie, Frédéric Schütz, Ping Cannon, Marjorie Liu, Xiaofeng Shen, Yoshiaki Ito, Wendy H Raskind, Marshall S Horwitz, Motomi Osato, David R Turner, Terence P Speed, Maria Kavallaris, Gordon K Smyth and Hamish S Scott
Conference Name
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 CBFβ, 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, CBFβ. 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2008 Michaud et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.