Immune Dysregulation leading to Acute Lymphoblastic Leukemia ('ID2ALL')

• Applicant: Katharina Gössling, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology ; Rheumatology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428917761

We hypothesize in this study that a dysregulated immune response against pathogens of common childhood infections favors the development of ETV6/RUNX1 positive B cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common type of leukemia of the childhood. Key objectives: I. Establishment and validation of the ‘ID2ALL’ experimental platform: To study infection-triggered immune responses peripheral blood mononuclear cells of healthy people shall be stimulated with typical antigens, children are commonly exposed to in early childhood. Bacterial (e.g. H. influenzae, S. pneumoniae), viral (e.g. RSV), fungal (e.g. Candida species) antigens and vaccines (e.g. Infanrix®) as well as toll like receptor ligands shall be used. Subsequent measurement of monocyte- and T cell-derived cytokines in the cell culture supernatant by ELISA will reflect a functional read-out for pathogen-specific innate and adaptive immune responses. PBMC subpopulations shall be analyzed using flowcytometry and clinical baseline parameters, such as immunoglobulin levels, shall be measured in the serum. II. Cytokine profiling and SNP analysis in ETV6/RUNX1 positive BCP-ALL patients and their parents compared to healthy control families (TRIO approach): The established assay will be used to characterize the innate and adaptive cytokine profile of 15-20 BCP-ALL patients with the ETV6/RUNX1 subtype after successful completion of the maintenance therapy and complete immunoreconstitution in comparison to an age-matched control cohort. Differences in the cytokine production shall be further deciphered by analysis of the corresponding signaling pathway. Single nucleotide polymorphisms in candidate genes of the underlying pathway will be analyzed to specifically determine genetic differences of the functionally relevant differences between patients and controls. III. Analysis of the influence of the detected immune dysregulation on leukemogenesis of ETV6/RUNX1 BCP ALL: To investigate the influence of the immune dysregulation on on the leukemogenesis, both an ETV6/RUNX1 leukemic cell line and primary murine Sca1-ETV6/RUNX1 bone marrow cells shall be used. Proliferation, apoptosis and autophagy shall be investigated under the influence by recombinant cytokines or other immunomodulators, dependent on the results in objective II. This will build the basis for the development of an in vivo mouse model to mimic immune modulation for prevention of BCP-ALL. IV. Bioinformatics prediction model for the cytokine profile of ETV6/RUNX1 patients: In parallel our collaboration partner will help to make use of an established bioinformatics model to predict cytokine responses using published SNP array data of an ETV6/RUNX1 patient cohort. Goal of this study is to understand the complex interplay of immunological and genetic factors in the development of ETV6/RUNX1 BCP-ALL. This study will give the experimental proof, to develop preventive immunomodulatory treatment strategies.

• DFG Programme: Research Grants