Discovering Protective Mutations in Midnolin: A Potential New Approach to Suppress B-Cell Cancers


UT Southwestern Medical Center researchers have identified a protein called midnolin as a potential target for suppressing B-cell leukemia and lymphoma in mice genetically predisposed to these cancers. By reducing or eliminating midnolin in these animals, researchers were able to prevent the development of these diseases without causing serious side effects.

The findings, published in the Journal of Experimental Medicine, could lead to new treatments for B-cell cancers that avoid the harsh side effects of current therapies. Dr. Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern, led the study.

Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of Toll-like receptors, used a genetic method called automated meiotic mapping (AMM) to trace the unusual features in mutant mice to the causative mutations. This approach helped identify genes essential for maintaining the normal physiologic state.

While mutations often lead to genetic diseases, they can also provide protection from diseases. For instance, protective mutations have been discovered in HIV-infected individuals and those with inherited sickle cell disease. These protective mutations have inspired drugs to treat various health conditions.

To search for protective mutations for Immune disorders, the researchers screened mutant mice for those with unusual features in their immune cells. In multiple sets of animals with unusually low numbers of B cells, the researchers used AMM to trace this deficit to mutations in midnolin, a protein primarily found in B cells.

Although complete absence of midnolin results in death during development, milder mutations, including those introduced using a genetic technique that allows deletion of the gene during adulthood, caused no apparent harm.

The researchers significantly reduced or completely eliminated midnolin in mice genetically predisposed to B-cell leukemias and lymphomas. While mice with normal midnolin died from these diseases by 5 months of age, most of those with less or no midnolin never developed the malignancies. This suggests that targeting midnolin could be an effective approach to suppressing B-cell cancers.

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