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.

Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome

“…Together these proteins form a transcription factor complex that is widely expressed in various hematopoietic lineages and regulates the expression of several critical genes. 3 Since the identification of RUNX1 as the causative gene in FPD/AML, 2 only 25 mutation-positive families have been reported in the literature, which suggests that FPD/AML is a relatively rare disorder. An additional explanation may be that this disorder is underdiagnosed, as was recently suggested by Owen et al, 1 who identified RUNX1 mutations in 50% (5/10) of families with more than one first degree relative with myelodysplastic syndrome (MDS) and/or AML.…”

“…1,2 Chronic lymphocytic leukaemia (CLL) is a B-cell malignancy with increased incidence among the elderly. The disease is due to an imbalance between cell death and proliferation resulting in an accumulation of malignant cells in the bone marrow and peripheral blood (reviewed in Van Bockstaele et al 3 ). Clinically, the disease varies from indolent, which may progress to/or appear at diagnostic as an aggressive incurable form.…”

“…Clinically, the disease varies from indolent, which may progress to/or appear at diagnostic as an aggressive incurable form. The most commonly used biological markers for the disease outcome are the type of chromosomal aberration and the mutational status of immunoglobulin heavy-chain variable region genes (IgV H ), often associated with the expression status of Zap70 tyrosine kinase (reviewed in Van Bockstaele et al 3 ). The telomere length and telomerase activity are further prognostic markers as unfavourable disease was associated with short telomeres 4 (reviewed in Van Bockstaele et al 3 ).…”

“…The most commonly used biological markers for the disease outcome are the type of chromosomal aberration and the mutational status of immunoglobulin heavy-chain variable region genes (IgV H ), often associated with the expression status of Zap70 tyrosine kinase (reviewed in Van Bockstaele et al 3 ). The telomere length and telomerase activity are further prognostic markers as unfavourable disease was associated with short telomeres 4 (reviewed in Van Bockstaele et al 3 ). This, together with altered expression of several telomeric components, 5 indicates that telomeres are profoundly rearranged in CLL cells.…”

MYB IS Required for B-Selection During Thymopoises

“…In addition, conditional deletion of Runx1 in DN2 thymocytes resulted in a partial block in DN3 to DN4 differentiation and impaired DN4 proliferation [284]. A gene expression microarray performed on Runx1-null embryos suggested that Runx1 targets also include genes involved in cell motility, cell proliferation, and cytoskeletal organization according to a biological pathway analysis [313]. Since we also detect altered expression of genes involved in similar …”