Research project
DC3 The noncoding face of the 3D genome of B-ALL
Our project aims to unravel the molecular mechanisms underlying the disease in the ~15% of B-cell acute lymphoblastic leukemia that has remained unclassified until now. To achieve this, we propose a novel approach that combines state-of-the-art genomic technologies and genome-engineering tools to identify and characterize noncoding mutations in unclassified B-ALL and understand their functional roles in the disease, paving the road for the development of new diagnostic and therapeutic strategies.
Keywords: oncoding mutation, 3D genome organization, B-ALL
Among the different types of leukemia, B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. While the cure rate in child is high, it declines with age to reach ~30% in adults. B-ALL comprises a large diversity of subtypes characterized and classified by genetic alterations more and less recurrent. In the past few years, the expansion of high throughput sequencing techniques has revolutionized our understanding of the genomic landscape of ALL by enabling a better characterization of genetic alterations allowing to refine the risk stratification and to identify new therapeutic targets. However, current leukemia mutation landscapes are far from complete and recurrent leukemia-associated genetic alterations cannot be identified in ~ 10 to 20 % of patients with B-ALL. With most somatic mutations occurring in noncoding regions, current understanding of cancer mutations will remain incomplete until a systematic examination of the noncoding genome is conducted. Although attributing a functional role to non-coding mutations has been challenging, recent studies have shown that non-coding mutations play a significant role in the development and progression of leukemia. They can modify gene expression and induce functional genomic changes by altering the binding of transcription factors or by inducing high-order chromatin structural modifications.
Thus, we propose a novel approach using multilevel genomic assays to simultaneously explore the 3D epigenome landscape and identify noncoding somatic mutations in unclassified B-ALL. The study aims to achieve three objectives through specific work packages:
For that, we will combine and integrate state-of-the-art genomic technologies and genome-engineering tools to identify and characterize noncoding somatic mutations in unclassified B-ALL and to characterize their functional roles in the disease.
This project will provide valuable insights into the disease’s mechanisms and may lead to the development of new diagnostic and therapeutic strategies.
Department of Pulmonary Medicine – Erasmus University Medical Center (Rotterdam, The Netherlands)