Project Details
Projekt
Modelling of oncogenic driver networks in molecular poor-response BCP-ALL
Applicant
Dr. Lorenz Bastian
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Acute lymphoblastic leukemia remains a therapeutic challenge in adult patients. - Especially in patients with poor therapeutic response or relapses, who currently only achieve long-term survival in 30% of cases, despite intensive chemotherapy and allogeneic stem cell transplantation. The aim of this project is to characterize two high-risk subtypes of acute lymphoblastic leukemia (Ph-like and ZNF384 ALL) with regard to leukemogenic mechanisms and potential therapeutic targets. Using CRISPR / Cas9 genome editing, functional models are to be created that recapitulate the genomic profile of the diseases in healthy murine lymphatic progenitor cells. Based on this in-vitro performed leukemogenesis, it will be analyzed which dependencies exist between genomic disease drivers and cooperating mutations. Gene expression profiles of these models will be compared with existing gene expression profiles of a representative cohort of patients with acute lymphoblastic leukemia as well as with healthy bone marrow donors. Using biostatistical models, signal networks will be identified that are essential for the development and maintenance of leukemia. Both, leukemia-typical regulations in general and specific signaling pathways that determine the gene regulation of the two high-risk subgroups are taken into account. Critical regulators of these signaling networks should then be switched off in the new cell line models in order to validate their relevance as a therapeutic targets. Finally, screening studies will identify molecular inhibitors that are suitable for inhibiting critical network regulators or downstream signals in order to eliminate the leukemia. Selected leukemia models will be transplanted into mice in order to test the most promising strategies in a model close to the clinical situation. Syngeneic transplantation models will allow for analysis of immune-mediated treatment effects. The models and methods used are an important resource for joint work within the clinical research group. New driver alteration candidates identified in P1 will be used for functional modelling and our models will be used to explore immunotherapeutic approaches (P5,P6). This project will contribute to an improved definition of gene-regulative processes in the development of leukemia in general. Specific therapeutic strategies will be identified, which form a basis for Phase-I studies in order to improve the prognosis for patients with high-risk ALL (Ph-like / ZNF348).
DFG Programme
Clinical Research Units
