Importance and function of Ikaros isoforms in the context of genotoxic chemotherapy

Genotoxic chemotherapy is a preeminent therapeutic option for Acute Lymphoblastic Leukemia (ALL), the most frequent childhood cancer. While therapy efficacy has seen improvements in recent years, a significant fraction of ALL patients still succumbs to this disease. Thus, it is critical to investigate mechanisms that influence treatment response in leukemias, including ALL.

Mutation or overexpression of dominant negative isoforms of the transcription factor Ikaros typifies a significant portion of high-risk ALL, and chronic lymphocytic leukemia (CML) at blast crisis. It is currently unclear whether the tumor suppressor Ikaros possesses functions outside or complementary to gene regulation that might influence carcinogenesis and response to treatment. Interestingly, the detection of DNA double-strand break marks is increased in hematopoietic cells whereby Ikaros is mutated. Preliminary results suggest that certain isoforms of Ikaros can rescue this phenotype in Ikaros mutated model cell lines. Thus, the absence of certain Ikaros isoforms could increase genomic instability. The aim of this project is to determine whether certain isoforms of Ikaros can promote genomic stability and thereby, influence the response to chemotherapy. The mechanism and functions exerted by Ikaros isoforms will be investigated.

For this study, we are using ALL and CML cell lines, and results obtained with these cells are compared to those obtained in hematopoietic cells of mouse models. We propose to define the effect of Ikaros disruption on genomic stability of hematopoietic cells when exposed to chemotherapeutic agents. Effect of the absence of Ikaros as well as the effect of different Ikaros isoforms on DNA repair mechanisms will be investigated. To define whether different isoforms of Ikaros could participate to DNA repair and exert specific nuclear activities, their protein interactome will be defined and compared when the cells are exposed or not to chemotherapeutic agents. To discriminate between direct and indirect effect of Ikaros isoforms on genomic stability, a comparative analysis of the genome wide recruitment of different Ikaros isoforms will be performed, and their effect of the transcriptome of hematopoietic cells at steady state or upon treatment with chemotherapeutic agents will be questioned.

Thus, this study will assess whether the Ikaros isoforms can have specific roles in modulating genomic stability, transcriptome in stress condition, and thus, the chemotherapy efficacy.

The current study involves a combination of high-throughput screenings, proteomics, molecular genetics, cellular and biochemical methods. In addition to perform experiments, the trainee will participate to experiment planification, result analyses and discussion regarding the orientation of the project. Guidance will also be provided for literature review and writing of scientific communications. The trainee will also attend and participate to lab meetings, HMR research center student’s seminars, international scientific presentations and meetings. English and French languages are used in the laboratory and the research center.

Funding category: Autre financement public

Fond de recherche des IRSC/CIHR

PHD Country: Canada