Structural variants induced by chemotherapy in leukemia cells

• Applicants: Professorin Irmela Jeremias, Ph.D.; Dr. Jan Korbel
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545519356

Chemotherapy plays a central role in the routine treatment of patients with acute leukemias (AL) and numerous anti-leukemia drugs eliminate tumor cells by inducing DNA damage. As an undesired effect, DNA-damaging drugs might induce genetic alterations in surviving AL cells, leading to treatment resistance and impaired patient prognosis. While treatment-induced single nucleotide alterations have been intensively studied, with TP53 as a prominent example, technical challenges have historically limited insight into structural variants (SV). SV are genomic alterations larger than 50–200 base pairs, the size of an average exon, and include translocations, inversions, insertions, and duplications/deletions, the latter commonly referred to as copy number alterations. SV are known for their important influence on tumor development and progression, with translocations present in most AL. Taking advantage of our novel technical advances, the present proposal aims for a better understanding of SV that are induced by chemotherapy and cause treatment resistance. We will (i) study different leukemia cell models such as primary tumor cells, patient-derived xenograft (PDX) cells, and cell lines; (ii) test different classes of DNA damaging chemotherapeutic drugs, which we will apply for (iii) different periods of treatment time, both short term and long term; (iv) and characterize resulting cells using cutting-edge single cell analysis techniques such as strand-specific DNA sequencing (Strand-seq), including scTRIP and scNOVA, which allow detection of SV in single cells and association with gene activity. For recurrent SV repeatedly emerging from the same genomic loci, their causative role for acquired treatment resistance will be investigated using state-of-the-art molecular functional approaches, such as CRISPR/CAS9-mediated gene editing. All in all, the planned work aims to identify chemotherapy-induced SV, which drive treatment resistance in AL. Such SV might serve as therapeutic targets and allow the development of novel treatment options to improve the prognosis of AL patients suffering from resistant disease.

• DFG Programme: Research Grants