Project Details
Projekt
Modeling of oncogenic driver networks in B-ALL – Impact of multilineage involvement
Applicants
Dr. Lorenz Bastian; Dr. Dennis Das Gupta
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Increased cellular plasticity is a hallmark of treatment resistance and high-risk disease across malignancies. Current advances in acute lymphoblastic leukemia (ALL) treatment mainly rely on lineage-specific immunotherapies (e.g., therapeutic antibodies, CAR-T cells). However, these therapies still fail frequently. The underlying mechanisms—particularly the role of cellular plasticity in immunotherapy escape—remain poorly understood. During the CRU’s first funding period, we discovered molecular subtypes within BCR::ABL1-positive ALL that link developmental origins to specific genomic and transcriptomic profiles. These subtypes showed distinct hematopoietic lineage involvement, with BCR::ABL1 being either restricted to lymphoid precursor cells (‘lymphoid-only’) in contrast to a multilineage involvement phenotype, with presence of BCR::ABL1 in hematopoietic stem cells or myeloid precursors. We adapted a novel single-cell RNA sequencing method (RoCK&ROI-Seq) to confirm these lineage patterns across hematopoiesis and to identify multilineage involvement also in exploration of other B-ALL subtypes (KMT2Ar, ZNF384r). Based on these findings, we hypothesize that multilineage driver involvement is a general phenomenon in B-ALL. We propose that subtype-specific secondary genomic aberrations, oncogenic transcriptional regulation, and varying transforming capacities across hematopoietic differentiation stages shape multilineage involvement. Guided by our first ‘multilinearity’ machine learning models, we will use RoCK&ROI-Seq to characterize the landscape of multilineage involvement across B-ALL subtypes. Integrated genomic and transcriptomic profiling will characterize the molecular underpinnings of this phenotype, which will be validated using our cohort of over 3,000 B-ALL transcriptomes. To study the functional basis of multilineage involvement, we will engineer murine hematopoietic stem cells and pre-B cells with leukemogenic driver fusions and additional genomic events from multilineage and lymphoid-only B-ALL cases. This will allow us to disentangle the contributions of the cell-of-origin, genomic drivers, and secondary events in developing multilineage phenotypes. These murine models will be treated in vitro and in vivo with immunotherapies (CD19xCD3 BiTEs and CAR-T cells) to assess how different genomic profiles affect therapy responses, which niches promote immune evasion, and what cellular adaptations occur under immunotherapy pressure. Our analyses will provide a comprehensive characterization of the molecular and cellular functions of multilineage involvement in B-ALL and its specific role in immunotherapy resistance. Predictive models based on these data will guide early identification of patients at risk of increased cellular plasticity and immunotherapy failure.
DFG Programme
Clinical Research Units
