Research

Max Planck Research Group Jachimowicz

Identification of therapeutic vulnerabilities and synthetic lethal strategies through genome instability syndromes

Together with our collaborators, we have established a unique cohort of individuals with previously uncharacterized hereditary disorders associated with genomic instability and premature aging. By integrating patient-derived material with genetically engineered cellular models and advanced sequencing technologies, we aim to uncover additional layers of DNA repair regulation and genome maintenance signaling.

An overview of biological heterogeneity, improvements in treatment, disease progression and mouse models in lymphomas.

To overcome major challenges in the identification of novel genomic instability syndromes — including subtle clinical phenotypes, limited diagnostic coverage, and labor-intensive functional validation — we developed an integrated discovery pipeline consisting of: (i) refined phenotype-driven patient identification, (ii) DNA repair-focused genomic and bioinformatic analyses, and (iii) high-throughput functional characterization using patient-derived primary cells and CRISPR/Cas9-engineered isogenic models.

Among our major discoveries are the identification and mechanistic characterization of the UBQLN4 deficiency syndrome and the UBQLN1 deficiency syndrome, two rare hereditary disorders caused by homozygous loss of UBQLN4 or UBQLN1, respectively. Both proteins belong to the Ubiquilin family and play central roles in DNA repair and genome integrity maintenance. Building on these findings, we further demonstrated that aberrant Ubiquilin expression promotes aggressive tumor phenotypes in human cancer. In particular, we discovered that UBQLN1-overexpressing tumors exhibit synthetic lethal sensitivity to PARP inhibition as well as increased responsiveness to immune checkpoint blockade, thereby revealing new therapeutic opportunities and potential diagnostic and prognostic biomarkers.

Current projects in the laboratory focus on defining the molecular functions of UBQLN1 in greater mechanistic detail and on translating these findings toward clinical application. In parallel, we continue to functionally characterize additional disease-causing alterations linked to genomic instability syndromes. Within this research area, we are active members of the DFG Research Unit FOR5504 “Physiological Causes and Consequences of Genome Instability”.

Identification of lymphoma signaling pathways and disease mechanisms

The second major focus of our laboratory is the investigation of signaling networks and disease mechanisms in B-cell lymphomas. By integrating longitudinal patient-derived data with advanced in vivo modeling approaches, we seek to connect molecular mechanisms with disease evolution, therapeutic response, and treatment resistance.

Flowchart for the investigation of genomic instability syndromes in patients using whole-genome sequencing, multi-omics analysis and functional validation.

Using primary lymphoma specimens, we perform comprehensive molecular profiling to better understand disease heterogeneity, clonal evolution, and lymphoma biology. To functionally extend these findings, we have established patient-derived cell lines, systemic xenograft models, and genetically engineered mouse models of B-cell lymphoma. These platforms enable mechanistic studies in physiologically relevant settings and provide a foundation for translational and therapy-oriented research.

Within this research focus, we are active members of the SFB1530 collaborative research center. In close collaboration with the clinical lymphoma program, we additionally lead and contribute to several translational and clinical studies.

Overall, our work combines high-resolution patient data, functional in vivo modeling, and translationally relevant experimental systems to define the biology of lymphoma and identify genotype-specific therapeutic strategies.