In a study by Yale Cancer Center, researchers report on the discovery of a common mechanism that promotes both autoimmune diseases and blood cancers, including the blood diseases Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). The results could help scientists better understand disease origin and progression in patients. The paper is published online today in the journal Molecular Cell.
“Our findings are very exciting in the field of both autoimmune disease and cancer, as they illustrate how pathogenic cells can ‘mis-use’ machinery from related cell types to cause disease and protect themselves from elimination,” said Markus Müschen, MD, PhD, Director of the Center of Molecular and Cellular Oncology and Arthur H. and Isabel Bunker Professor of Medicine (Hematology) at Yale Cancer Center, and senior author of the study.
B cells and T cells are key components of our immune system, and have each evolved very similar cellular machinery to carry out their function. B cells utilize a protein called SYK, whereas T cells utilize a protein called ZAP70, which act to activate the signaling networks required to allow the B cells and T cells to develop and mount an effective immune response while avoiding the development of autoantibodies. Similarly, B cells have developed protective mechanisms, which screen for pathogenic or defective cells that if left unchecked would give rise to leukemia, a process which researchers have shown in previous studies was highly dependent on having the ‘right amount’ of the protein SYK. In this study, by performing large scale analyses of patient data and a highly advanced single-cell technology, researchers discovered that compared to normal B cells which only express SYK, B cells from patients with B cell leukemia and some lymphomas also expressed ZAP70. Even though SYK and ZAP70 are structurally very similar proteins, scientists found they perform quite differently. Strikingly, the results showed that when expressed in B cells, ZAP70 physically competed with SYK and was able to ‘turn off’ the pathways that would normally signal that the B cell is autoreactive or malignant and should be eliminated. When the Yale researchers tested this in models of disease, they found that engineering the expression of ZAP70 in B cells rapidly drove the development of autoimmune disease and leukemia, and that preventing this, was sufficient to reduce the progression of disease.
“We think the findings from our study in B cells may help guide us in understanding how the two proteins could also be involved in promoting lymphomas of the T cell lineage,” said Teresa Sadras, PhD, formerly a member of the Müschen Lab and lead author of the study. “Moving forward, we are interested in exploring what happens when T cells, which normally only have ZAP70, also express SYK, to help us further understand these difficult diseases.”
The study is funded by the National Institutes of Health (NIH) through a National Cancer Institute (NCI) Outstanding Investigator Award, the Howard Hughes Medical Institute, The Leukemia & Lymphoma Society, The Mark Foundation for Cancer Research, The Paul G. Allen Frontiers Group, and the V Foundation for Cancer Research.
Eric Meffre, PhD, from Yale is also co-author of the study.