Integrative analysis of RUNX1 downstream pathways and target genes
1 Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia
2 Department of Medical Biology, The University of Melbourne, 3050 Parkville, Victoria, Australia
3 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia
4 Division of Medical Genetics, University of Geneva Medical School, 1211 Geneva, Switzerland
5 Experimental Therapeutics Program, Children's Cancer Institute Australia for Medical Research, 2031 NSW, Australia
6 Department of Hematology and Genetic Pathology, School of Medicine, Flinders University, 5001 South Australia, Australia
7 Molecular and Cell Biology, National University of Singapore, 117543 Singapore
8 Division of Medical Genetics, University of Washington, Seattle, USA
9 Center for Integrative Genomics, University of Lausanne, Switzerland
10 Internal Medicine, University Hospital, Berne, Switzerland
11 Université de Lyon, Lyon, F-69008, France; Université Lyon 1, Domaine Rockfeller, Lyon, F-69008, France
12 CNRS UMR 5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, Lyon, F-69008, France
13 Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
14 Division of Molecular Pathology, the Institute of Medical and Veterinary Science and The Hanson Institute, Box 14 Rundle Mall Post Office, Adelaide, SA 5000, Australia
15 The School of Medicine the University of Adelaide, SA, 5005, Australia
BMC Genomics 2008, 9:363 doi:10.1186/1471-2164-9-363Published: 31 July 2008
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.
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.
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.