Single-cell genetics of B cell development and leukemia. Combining single-cell metabolomics analyses with forward genetics screening based on CRISPR/Cas9 techniques (Schjerven et al., J Exp Med 2017), the Müschen laboratory developed a platform to identify metabolic vulnerabilities of relapse clones in remission samples from leukemia patients (Chan et al., Nature 2017).
Role of infection in clonal evolution of B cell malignancies. In collaboration with Mel Greaves, Müschen’s group demonstrated that the Immunoglobulin mutator enzyme AID drives clonal evolution towards B-cell leukemia in the context of acute infections (Greaves & Müschen, Cancer Discov 2016). In animal models that recapitulate inflammatory stimuli related to infections, his group demonstrated the critical role of AID and explained how infection can drive clonal evolution of dormant preleukemic cells (Swaminathan et al., Nature Immunol 2016).
Discovery and targeted therapy for a novel subset of acute lymphoblastic leukemia (ALL). In a multicenter study of >800 cases of ALL, Müschen’s group discovered a new subtype (~15% of all cases), that critically depends on active pre-B cell receptor signaling (pre-BCR; Buchner et al., Nature Comm 2015) and identified the tyrosine kinase inhibitor dasatinib as a potent pre-BCR antagonist, showing that patients with pre-BCR-dependent disease benefit from treatment with dasatinib (Geng et al. Cancer Cell 2015).
BCL6 mediates a novel form of drug-resistance. Müschen’s group discovered that leukemia cells increased BCL6 levels by ~2-3 log orders in response to tyrosine kinase inhibition (TKI). To test the role of BCL6 in TKI-resistance, his group generated a new floxed mouse model for conditional ablation of BCL6. Ablation of BCL6 restored drug-sensitivity and prevented recurrence of disease in an in vivo disease model (Duy et al., Nature 2012 and Swaminathan et al., Nature Medicine 2013).
Discovery of autoimmunity checkpoints as new target in B-cell tumors. In a series of three recent studies, researchers led by Müschen’s group discovered that despite oncogenic transformation, basic mechanisms to eliminate autoreactive B-cells are still functional in B cell leukemia (Shojaee et al., Nature Medicine 2016) and lymphoma (Shojaee et al., Cancer Cell 2015). Reliable activation of autoimmunity checkpoints and induction of cell death can be achieved by pharmacological hyperactivation of B-cell receptor signaling (Chen et al., Nature 2015).