It is largely unclear which disease- and (immune) microenvironment-specific factors define an almost linear relationship between increasing age and poorer outcome. One reason is the increasing incidence of BCP-ALL harboring the BCR-ABL1 gene fusion with age. Another factor is higher treatment toxicity. In all patient groups, somatic structural DNA rearrangements and sequence mutations affecting genes involved in lymphoid development, cytokine receptor and kinase signaling, tumor suppressors and chromatin modification classify patients into high-risk groups – even though a favorable genetic aberration in children may not be favorable in adults and vice versa. Tackling this barrier and identifying mechanisms of disease persistence across age groups to guide age-overriding molecular-driven therapy is a unique contribution of this proposed CRU.
In all patients, irrespective of age, minimal residual disease (MRD) persisting in the bone marrow is the most important adverse prognostic factor. It is commonly believed that a patient´s immune system plays a role in keeping MRD in check, which is the rationale for performing allogeneic stem cell transplantation. However, no systematic studies on the contribution of the immune system controlling residual leukemia in ALL have been conducted. We suspect that age differences in immune control may largely contribute to the discordant outcomes in patient populations at different ages. This CRU aims to investigate the age specific immune-leukemia interaction status in addition to the molecular dissection of the leukemic cells. Importantly, the CRU will translate results into the design of novel tailored immunotherapy approaches. Preclinical testing in sophisticated models and clinical application of novel findings into patient care will be pursued (Z project).
Kiel has a unique infrastructure characterized by the presence of the major ALL study groups AIEOP-BFM (pediatric) and GMALL (adult) with published expertise, the Institute of Clinical Molecular Biology (IKMB), innovative preclinical models and engineering approaches for immunotherapies. The IKMB in Kiel has an internationally renowned infrastructure and uses cutting-edge technology involved in a number of DFG-funded projects. ALL will serve as a model disease overriding age in clinical care and basic research. The combined molecular characterization of the leukemic cells and immune control mechanisms will ultimately identify novel and more precise intervention strategies.