Markus Müschen
Yale University, CT·Microbiology & Immunology
The body makes millions of antibody-producing B cells every day, and many of them would attack the body's own tissues. A built-in quality-control system removes these dangerous cells to prevent autoimmune disease.
- Fields
Microbiology & Immunology
Medicine & Clinical Research
Genetics
- Topics
B-cell malignancies
leukemia
lymphoma
- Grants
- 5 known grants, through Jun 2029
What they work on
- Test whether persistent PI3K signaling, a growth pathway, forces B-ALL, CLL and mantle cell lymphoma cells to grow too large and run out of ATP, triggering energy crisis and central-tolerance elimination.
- Determine how high-frequency calcium pulses inside B cells are read by NFAT, a protein that drives anergy and cell death, and whether this route can be exploited to kill B-cell tumors.
- Test the "metabolic gatekeeper" idea by engineering B cells to inducibly enlarge and gain mitochondria, and by over-activating B-cell-receptor kinases, to see how energy limits govern malignant transformation.
- Use long-term single-cell mass measurements to test whether lymphoma cells cycle between BCL6-marked rest and MYC-marked growth, and whether the rest phase is needed for recovery and survival.
- Uncover how the T-cell kinase ZAP70, when wrongly made in B cells, slows SYK-driven calcium pulses and shifts signaling from NFAT to NF-κB, the cell's survival switch.
- Use genetic mouse models of B-ALL, CLL and autoimmunity to test how ZAP70 lets self-reactive and pre-cancerous B cells escape negative selection and become malignant.
- Dissect how GSK3B, CK1a, NAE1 and immunoproteasome subunits PSMB8/PSMB9 break down beta-catenin protein so efficiently in B cells, and how blocking them kills B-lymphoid cells.
- Define how beta-catenin pairs with Ikaros factors and the NuRD repressor complex to turn off MYC, a growth gene, in B cells, explaining why beta-catenin build-up is toxic to them.
- Repurpose clinically tested GSK3B inhibitors to trigger beta-catenin build-up and MYC repression in drug-resistant B-cell leukemias and lymphomas, using patient-derived xenograft models.
More about the research
The lab's central finding is that this same system can also kill B-cell cancers, especially leukemias and lymphomas that start early in B-cell development. Those cancers include B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, plus chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), which remain incurable in adults. Current drugs that block signaling enzymes (kinases) help, but cancers eventually become resistant. Across five projects, the lab asks how B cells sense dangerous signals, energy stress and protein levels, and how these weak points could be turned into new treatments.
Why it matters
About 1.4 million people in the U.S. live with or are recovering from B-cell malignancies. B-ALL, CLL and mantle cell lymphoma often relapse after kinase-inhibitor treatment. Turning the body's own B-cell quality-control system against these cancers could overcome drug resistance with fewer side effects. Repurposing GSK3B inhibitors, which already have favorable safety records in clinical trials, could speed new options for patients with refractory disease. The same insights may also inform new treatments for B-cell autoimmune disorders.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Randall Davis
University of Alabama at Birmingham, AL·Microbiology & Immunology
Determine how FCRL1, a B cell surface receptor overproduced in leukemia, influences B cell responses in human and mouse disease models of chronic lymphocytic leukemia and immune tolerance.
Lili Wang
Columbia University, NY·Medicine & Clinical Research
Determine how the MGA/MYC/NME1 pathway, a growth program switched on when the gene Mga is silenced, changes tumor-cell properties during the CLL-to-Richter's transformation, using the lab's mouse RT model.
Jonathan Coloff
University of Illinois Chicago, IL·Biochemistry
Determine whether luminal breast tumors, which cannot make the amino acid serine, shrink or stop growing when mice are fed a serine-free diet.
The school
Yale University: 73 labs on PI Pages, $1.5B a year on research, 438 research doctorates a year.
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