City of Hope Researchers Find “Achilles' Heel” in B Cell Tumors

March 14, 2018 | by Katie Neith

breakthroughs - markus muschen Markus Müschen, M.D., Ph.D.
B cells are a type of white blood cell known for producing antibodies in the human immune system and play an important role in the immune defense against infections caused by viruses or bacteria.
 
However, the ability of B cells to make antibodies through a series of DNA-recombination events comes with the risk of DNA lesions that may cause malignant transformation and cancer. In B cells, cancer-causing aberrations typically result in leukemia and lymphoma.
 
In a new paper published today in the journal Cell, a team of researchers led by City of Hope’s Markus Müschen, M.D., Ph.D., chair of the Department of Systems Biology and holder of The Norman and Sadie Lee Foundation Professorship in Pediatrics, and Gang Xiao, Ph.D., assistant research professor in the Department of Systems Biology, report on the discovery of a new therapeutic target for these B cell malignancies.
 
All cells need energy to survive. But the team found — through a series of studies in animal models — that B cells and B cell-derived tumors convert sugar and nutrients into energy in a way that is fundamentally different from other cells. The process involves an enzyme called PP2A and its newly discovered ability to redirect energy metabolites from sugars into a pathway that generates antioxidants to protect cells from damage during metabolism. 
 
Anna Hecht de Gutierrez Gang Xiao, Ph.D.
In other cell types, PP2A is dispensable because other molecules can provide antioxidant protection. In contrast, B cells and B cell leukemia and lymphoma cells critically depend on PP2A. When the researchers removed PP2A in B cells through genetic deletion of the PP2A gene, this had little effect on other cells but induced acute death in B cell leukemia and lymphoma cells.
 
“Other cells try to balance generation of building blocks for growth with protection against oxidative stress, which can cause damage to the cells,” said Müschen, corresponding author on the paper. “In B cell tumors, this balance is heavily tilted toward growth, so these cells are very sensitive to oxidative stress.”
 
This makes B cell tumors, including leukemia and lymphoma, vulnerable, according to Xiao. “In our paper, we show several new strategies of how this vulnerability can be targeted to kill B cell tumors but spare normal cells,” he said. 
 
One such strategy is a drug that can further skew the balance in energy metabolism by targeting PP2A. It is called LB-100 and is already in a clinical trial at City of Hope.
 
“We think that the same mechanism used to target B cell tumors could also work in autoimmune diseases, in which uncontrolled B cells make self-destructive antibodies causing type 1 diabetes, lupus, rheumatoid arthritis and other serious diseases,” Müschen said. “We think that targeting this pathway with LB-100 and similar drugs may be beneficial for patients with B cell tumors, as our paper shows, but perhaps also for patients with B cell autoimmune diseases.”
 
“The unique way that B cells and B cell-derived tumors consume glucose encourages us to discover more regulating molecules in addition to PP2A, which was identified in this study,” Xiao added. “As we accumulate this type of knowledge, we may be able to exacerbate the vulnerability of B cell tumors and/or improve the fitness of normal lymphocytes in the immune system to help them defend our bodies.”
 
Müschen and Xiao worked with others at City of Hope and collaborators from UCLA, UC San Francisco, Jena University in Germany, the University of British Columbia, Dana Farber Cancer Institute and Harvard Medical School on the studies and resulting Cell paper, “B Cell-specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies.” 
 
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