Research & Publications
To prevent production of harmful autoantibodies and autoimmune disease, autoreactive B-cells are eliminated by a process termed negative selection. In recent years, our laboratory established new conceptual frameworks for the understanding of B-cell signaling mechanisms and negative selection. Contrary to established dogma, these mechanisms are not only active in preventing autoimmune disease but also represent an emerging class of therapeutic targets in malignant B-cell tumors.
- We discovered regulation of energy-abundance as the central determinant of negative B-cell-selection: Hyperactivation of kinases downstream of an autoreactive B-cell receptor induces ATP-depletion and energy stress.
- Studying changes of energy-metabolism during B-cell transformation, we discovered that glucose carbon-flux was diverted in way that left transformed B-cells uniquely vulnerable to inhibition of PP2A, an enzyme that coordinates glycolytic flux with antioxidant protection.
- We discovered that changes in cell-size are orchestrated by BCL6 and MYC. Opposed by MYC, BCL6 decreases cell-size by transcriptionally repressing glucose-uptake in favor of autophagy.
- Tracking mechanisms of leukemia-initiation in 1,100 patients, we developed the paradigm of ‘pathway convergence’. Only mutations that converged on one central pathway promoted leukemia-progression. Genetic reactivation of divergent (suppressed) pathways engaged conflicting biochemical and transcriptional programs and subverted leukemia-development. Pharmacological pathway-reactivation to create a diverse signaling-environment represents a novel strategy to prevent leukemia-progression.
- Studying biophysical mechanisms of B-cell activation, we discovered the short endosomal protein IFITM3 as central scaffold for lipid-raft assembly and surface-expression of rafts-associated receptors. Membrane-recruitment of IFITM3 was essential for the initiation of PI3K-signaling, antibody affinity maturation and oncogenic B-cell transformation.
- Drug discovery tool for selective targeting of B-cell malignancies: We developed an interactive computational tool (lymphoblasts.org) to identify novel B-cell selective vulnerabilities based on integrated genetic and pharmacological compound screens. Compound screening data from CTD and GDSC databases were reprocessed by fitting 4-parameter log-logistic dose response curves. Differential gene-dependency was also tested using DEMETER2 and Chronos scores, from Project Achilles RNAi and CRISPR datasets, respectively. To prioritize cell-type specific targets, compounds were ranked by average differential rank percentile of both compound-sensitivity and target-gene dependency.
Extensive Research Description
Since 2009, the Müschen laboratory has established new conceptual frameworks for the understanding of B-cell signaling and energy metabolism and how defects in these mechanisms contribute to autoimmunity and B-cell transformation. Influenced by his postdoctoral training in basic immunology (Klaus Rajewsky and Ralf Küppers) and cancer genetics (Janet D. Rowley), Dr. Müschen is particularly interested in signal transduction pathways that change the clinical trajectory of human B-cell malignancies and B-cell driven autoimmune diseases. To generate hypotheses and for target discovery, his laboratory builds on clinical outcome predictors: in collaboration with multiple study teams across the US, his group developed and validated phenotypic biomarkers of favorable and poor clinical outcomes in B-cell malignancies and integrated these markers into models of oncogenic signaling pathways. As PI of the NCI CTEP ‘Human hematopoiesis and leukemia PDX’ program, his laboratory developed PDX resources to model B-cell malignancies based on patient-derived cells and cord blood-based humanized mouse models to study mechanisms of human B-lymphopoiesis in vivo.
In 2010, Dr. Müschen joined the University of California San Francisco (UCSF) as full professor with tenure and served as Program Leader of the Hematological Malignancies Program at the UCSF Comprehensive Cancer Center. He is currently a Howard Hughes Medical Institute (HHMI) Faculty Scholar and supported by an NCI Outstanding Investigator Award (R35). The Müschen laboratory consists of 18 trainees and staff. So far, 16 of his former trainees have become tenured or tenure-track faculty in academic research at institutions including UCSF, Imperial College, University of Pennsylvania, Stanford University, WEHI, TU Munich, SIBS Shanghai, Penn State and University of Cologne. At Yale University, Dr. Müschen serves as Director of the Center of Molecular and Cellular Oncology and as a mentor for six junior faculty.
Antibody Affinity; Antibody Specificity; Arthritis, Rheumatoid; Autoimmune Diseases; Autophagy; B-Lymphocytes; Burkitt Lymphoma; Cell Adhesion; Cell Communication; Cell Cycle; Cell Division; DNA Damage; Endocytosis; Energy Metabolism; Genes, Immunoglobulin; Hematologic Diseases; Hodgkin Disease; Immunity; Immunologic Deficiency Syndromes; Leukemia; Leukemia, Hairy Cell; Lupus Nephritis; Lymphocyte Cooperation; Lymphocyte Activation; Lymphoma; Lymphoma, Follicular; Lymphomatoid Granulomatosis; Metabolism; Mycosis Fungoides; Oxygen Consumption; Phosphorylation; Preleukemia; Receptor Aggregation; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Sjogren's Syndrome; Gene Rearrangement; Signal Transduction; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Prolymphocytic, T-Cell; Leukemia, Prolymphocytic; Lymphoma, B-Cell; Lymphoma, T-Cell; Lymphoma, Large-Cell, Immunoblastic; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell, Cutaneous; Lymphoma, AIDS-Related; Cellular Senescence; Cell Death; Lymphoma, Large-Cell, Anaplastic; Lymphomatoid Papulosis; Antigen Presentation; Oxidative Stress; Lymphoma, B-Cell, Marginal Zone; Molecular Mimicry; Cell Respiration; Cell Lineage; Lymphoma, Mantle-Cell; Lupus Vasculitis, Central Nervous System; Cell Size; Carbohydrate Metabolism; Lipid Metabolism; Genes, Immunoglobulin Heavy Chain; Activating Transcription Factors; Leukemia, Large Granular Lymphocytic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Neoplasms, Plasma Cell; Leukemia, Prolymphocytic, B-Cell; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Lymphoma, Primary Effusion; Metabolome; Rheumatoid Vasculitis; Autoimmune Lymphoproliferative Syndrome; Enteropathy-Associated T-Cell Lymphoma; Composite Lymphoma; Wnt Signaling Pathway; Clonal Evolution; Clonal Selection, Antigen-Mediated; Immunoreceptor Tyrosine-Based Activation Motif; Optogenetics; Cellular Reprogramming; Plasmablastic Lymphoma; Oncogene Addiction; Cell Competition
Public Health Interests
Biomarkers; Cancer; Clinical Trials; Evolution; Genetics, Genomics, Epigenetics; Immunology; Metabolism; Metabolomics