Transcriptional dysregulation mediated by RUNX1-RUNX1T1 in normal human progenitor cells and in acute myeloid leukaemia.
The t(8;21)(q22;q22) occurs frequently in acute myelogenous leukaemia and gives rise to the transcription factor fusion protein, RUNX1-RUNX1T1 (also known as AML1-ETO). To identify the genes dysregulated by the aberrant transcriptional activity of RUNX1-RUNX1T1, we used microarrays to determine the effect of this mutation on gene expression in human progenitor cells and during subsequent development. Gene signatures of these developmental subsets were very dissimilar indicating that effects of RUNX1-RUNX1T1 are highly context dependent. We focused on gene changes associated with the granulocytic lineage and identified a clinically relevant subset of these by comparison with 235 leukaemia patient transcriptional signatures. We confirmed the overexpression of a number of significant genes (Sox4, IL-17BR, CD200 and gamma-catenin). Further, we show that overexpression of CD200 and gamma-catenin is also associated with the inv(16) abnormality which like RUNX1-RUNX1T1 disrupts core binding factor activity. We investigated the functional significance of CD200 and gamma-catenin overexpression in normal human progenitor cells. The effect of IL17 on growth was also assessed. Individually, none of these changes were sufficient to recapitulate the effects of RUNX1-RUNX1T1 on normal development. These data provide the most comprehensive and pertinent assessment of the effect of RUNX1-RUNX1T1 on gene expression and demonstrate the highly context-dependent effects of this fusion gene.
Tonks
A
A
Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK. tonksa@cf.ac.uk
Pearn
L
L
Musson
M
M
Gilkes
A
A
Mills
K I
KI
Burnett
A K
AK
Darley
R L
RL
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D019070:Cell Lineage; D002478:Cells, Cultured / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000648:ultrastructure; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D051180:Desmoplakins / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D055751:SOXC Transcription Factors; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D014178:Translocation, Genetic; D051185:gamma Catenin / Q000235:genetics / Q000502:physiology
C107844:AML1-ETO fusion protein, human; D015703:Antigens, CD; D050676:Core Binding Factor Alpha 2 Subunit; D051180:Desmoplakins; D006609:High Mobility Group Proteins; C495292:JUP protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000075142:RUNX1 Translocation Partner 1 Protein; D053722:Receptors, Interleukin-17; D011993:Recombinant Fusion Proteins; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D015534:Trans-Activators; D051185:gamma Catenin; C042739:antigens, CD200