Investigation of the Impact of UBTF Mutations on Leukemogenesis of Pediatric Acute Myeloid Leukemia

Pediatric acute myeloid leukemia (AML) is a hematological cancer associated with poor prognosis.

Despite the best available treatment, many children experience a relapse that in most cases is lethal, and new therapeutic options are needed to improve patient outcome.For a better understanding of the underlying causes of AML relapse and therapy resistance, we performed multiomics analyses of diagnosis and relapse AML samples from 25 children.

We found recurrent mutations in the transcription factor gene UBTF that due to their architecture have been proven to be underreported in the scientific literature.

The aim of this project is to functionally evaluate the role of UBTF mutations in leukemogenesis to find new therapeutic options.We will employ cell lines, patient derived xenografts and primary murine hematopoietic cells to investigate the effect of UBTF mutations on cellular fitness, leukemia onset and resistance.

First, we will perform cell based in vitro assays.

These include examination of differences between UBTF-mutant and wild type cells with regards to the UBTF-DNA interactome via ChIP-seq, the transcriptome via RNA-seq and the proteome via mass spectrometry to find new drug targets.

Thereafter, in vivo mouse modeling will be conducted to investigate the impact of UBTF mutations in leukemogenesis.Our studies have great potential to provide critical insights into AML biology. Ultimately, our findings will hopefully lead to more effective treatment of children with AML.