Our group is interested in comparative analyses of normal lymphocyte development and malignant transformation towards leukemia and lymphoma. We cover research areas with relevance to Immunology, Hematology and Cancer Biology. Our research involves experiments with primary human leukemia and lymphoma cells, normal lymphocyte development in humanized mice, leukemia, lymphoma and stem cell transplantation pre-clinical 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.

Recent work of the laboratory:
• 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 Nature 2021).
https://medicine.yale.edu/lab/muschen/
@muschenlab