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Disruption of transcription regulatory networks in childhood Acute lymphoblastic leukemia
Sadílek, Vojen ; Fišer, Karel (advisor) ; Frič, Jan (referee)
Transcription factor aberrations are the initiating lesion in a majority of pediatric Acute Lymphoblastic Leukemia (ALL) cases, often acquired in utero. These mutations play a crucial role in determining the disease phenotype and prognosis. This work advocates for a broad evaluation of the transcriptomic landscape from the viewpoint of transcription factors and their targets. We adapted SCENIC (Aibar et al., 2017), a tool for single-cell gene regulatory network inference, for an extensive dataset of 633 bulk RNA sequencing samples of pediatric ALL. This allows us to evaluate the gene expression profile as a result of transcription factor activity. Furthermore, we aimed to deepen our understanding of valuable preexisting data by incorporating information from several "-omics" databases. We utilized resources of single cell RNA sequencing data, protein-protein interactions and putative cis-regulatory elements in our analysis. Our approach covers the transcriptomic landscape without an overt bias for differentially expressed or highly variable genes. We demonstrate that most B-ALL subtypes have specific patterns of transcription factor activity and, for subtypes initiated by transcription factor mutations, we examine the influence of such aberrations on their activity. With MEF2D as an example, we...
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