Markus Müschen serves as Arthur H. and Isabel Bunker Professor of Hematology and Director of the Center of Molecular and Cellular Oncology at Yale. He is currently a Faculty Scholar of the Howard Hughes Medical Institute (HHMI) and supported by an NCI Outstanding Investigator Award (R35).
The Müschen laboratory uses pharmacological agents to leverage B-cell selection for targeted cancer therapy. Studying more than 800 patients, they discovered a new subtype of ALL (~15%) that critically depends on pre-B-cell receptor signaling, which can be blocked by dasatinib (Cancer Cell 2015). In addition, the Müschen laboratory provided a mechanistic explanation for the known epidemiological link between infections and leukemia-risk: Aberrant activation of the B-cell mutator enzyme AID in the context of infections drives clonal evolution of normal B-cells towards leukemia (Nature Immunology 2016). Dr. Müschen’s group discovered that B-cell tumors are subject to a unique autoimmunity checkpoint for removal of self-reactive B-cells. Targeted hyperactivation of SYK (Nature 2015), PI3K (Nature Medicine 2016) and ERK (Cancer Cell 2015) in B-cell malignancies represents the functional equivalent of an autoimmunity checkpoint (AIC) to prevent B-cell autoimmunity. AIC-activation is achievable by pharmacological hyperactivation of SYK, PI3K and ERK, thereby leveraging mechanisms of negative selection in the immune system for targeted cancer therapy (Nature Rev Cancer 2018). Most recently, the Müschen laboratory identified a novel B-cell transcriptional program for repression of glucose and energy supply. The B-lymphoid transcription factors serve a novel gatekeeper-function by limiting energy-supply to levels that are insufficient to fuel oncogenic transformation (Nature 2017). The full range of metabolic gatekeeper functions of B-cell transcription factors, including their ability to suppress the pentose phosphate pathway (PPP) in B-cell malignancies was revealed in a follow-up study by the Müschen laboratory (Cell 2018).