How B cell tumors get fit
Many tumor diseases are caused by an overexpression and deregulation of signaling proteins promoting the prolonged survival and continuous growth of cells. This is also the case for the most frequent hematological tumors in humans namely B cell leukemia or lymphomas also called blood cancer. These tumors often employ the signaling pathways of the B cell antigen receptor (BCR) and its coreceptor CD19 for their extensive growth and metabolic fitness. How exactly these tumors combine BCR and coreceptor signaling was so far unknown. The research team led by Prof. Dr. Michael Reth and including Dr. Jianying Yang and Dr. Xiaoxui He has now discovered a new pro-survival receptor module on the surface of the human Burkitt lymphoma B cell line Ramos. The scientists have published these findings in the EMBO Journal.
The BCR plays an essential role for the clonal selection and antigen-dependent expansion of B cells resulting in antibody production after an infection or immunization. The BCR is a multi-protein complex consisting of the membrane-bound immunoglobulin (mIg) and the Igα/Igβ (CD79a/CD79b) heterodimer, the two components of which each contain an immunoreceptor tyrosine-based activation motif (ITAM) that connects the receptor to protein tyrosine kinases and several cytosolic signaling pathways. On the surface of activated B cells the BCR cooperates with the BCR co-receptor molecule CD19 in the activation of the PI3K signaling pathway, which promotes B cell proliferation and survival. To learn more about how these two receptors influence the fitness and growth of human B cell tumors, the group employed the CRISPR/Cas9 technology that allows efficient gene deletion in human cell lines. With this method, they deleted the genes encoding the four components of the BCR (heavy chain, light chain, Igα and Igβ) and the CD19 co-receptor molecule in the human Burkitt lymphoma cell line Ramos. They discovered that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b) and the BCR co-receptor CD19 for their fitness und competitive growth in culture. Furthermore, they found that in the absence of any other BCR component, Igβ is expressed as a homodimer on the B cell surface where it is found in close proximity to CD19 and signals in an ITAM-dependent manner. These data suggest that Igβ and CD19 are part of an alternative B cell signaling module that uses continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells. The discovery of a new pro-survival signaling module on a human tumor cell is a success of the nanoscale explorer and oncogenic signaling program of BIOSS.
Michael Reth is the speaker of the cluster of excellence BIOSS Centre for Biological Signalling Studies and Jianying Yang is a group leader at the Institute of Biology III of the Faculty of Biology. After a successful postdoc in Freiburg Dr. Xiaoxui He is now pursuing her scientific career at the La Jolla Institute for Allergy and Immunology in San Diego, USA
He X, Kläsener K, Iype JM, Becker M, Maity PC, Cavallari M, Nielsen PJ, Yang J, Reth M.
EMBO J. 2018 Apr 18. pii: e97980