Yale University New Haven, CT, USA
Our group is interested in comparative analyses of normal lymphocyte development and malignant transformation towards leukemia. We cover research areas with relevance to Immunology, Hematology and Cancer Biology. Our research involves experiments with primary human leukemia cells, normal lymphocyte development in humanized mice, leukemia and stem cell transplantation models, mouse genetics, gene editing, genetic biosensors of signal transduction, optogenetics, classical molecular and cell biology, a strong emphasis on mechanistic studies in oncogenic signal transduction. We strive to promote a culture of diversity and inclusivity, focusing on career development and innovative approaches to science.
Flow cytometry, mass spectrometry/quantitative phosphoprofiling, genetic biosensors of signal transduction, optogenetics, mouse genetics, bone marrow transplantation assays, retroviral gene delivery, whole exome sequencing and RNA-seq-analysis of clonal evolution of leukemia, pre-clinical drug testing in xenotransplantation models.
Recent work of the laboratory:
To prevent the production of harmful autoantibodies and autoimmune disease, autoreactive B-cells and pre-malignant clones are eliminated by a process termed negative selection. Despite strict and rigorous negative selection, B-cells frequently give rise to autoimmune diseases and B-cell malignancies such as leukemia and lymphoma. Since humans can live without B-cells for extended periods of time, the Müschen laboratory systematically investigated lineage-specific vulnerabilities that are common in B-cell leukemia/lymphoma but not any other cell type. Contrary to established dogma, these mechanisms are not only active in preventing autoimmune disease but also represent a novel class of therapeutic oncogenic targets in malignant B-cell tumors. Over the past five years, the Müschen Laboratory established innovative conceptual frameworks for the understanding of B-cell signaling mechanisms and negative selection, some of which are summarized under 'featured publications'.
PhD in cell or molecular biology, enthusiasm for science, willingness to think beyond established concepts and to try and learn new experimental and analysis tools. The lab takes a team science approach, being collaborative is important as well.
• 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 (Chen Nature 2015, Shojaee Nature Med 2016, Chan Nature 2017; Pan PNAS 2020).
• 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 (Xiao Cell 2018).
• 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 (Duy Nature 2012; Geng Cancer Cell 2015; Hurtz Genes & Dev 2019).
• Tracking mechanisms of leukemia-initiation in 1,100 patients, we discovered pathway convergence as a novel therapeutic vulnerability in B-ALL. 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 B-ALL relapse and drug-resistance (Chan Nature 2020).
• 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 (Lee et a. Nature 2020).