The lymphatic system is part of the body’s immune system and functions as one of the body’s defense systems against infections. Lymphocytes are white blood cells located in the lymph fluid, which play an essential role in protecting our body from infections and diseases. Lymphocytes originate from bone marrow stem cells. B-cell lymphocytes mature in the bone marrow or in lymphatic organs, whereas T-cell lymphocytes mature in the thymus. Lymphoma, or lymphatic cancer, originates in lymphocytes that become abnormal or mutated. These lymphocytes’ division mechanism is disrupted, leading to their uncontrolled proliferation. These lymphocytes may separate from their original location, penetrate the blood stream and reach various organs.
Somatic hypermutation (SHM) is one of the mechanisms by which genes in B cells are modified to generate a large repertoire of B lymphocytes, each expressing a unique antibody molecule. The SHM process involves two steps: first, genetic mutations are generated by the mutation initiating enzyme AID (activation-induced deaminase); Second, DNA repair enzymes spot the changes and begin making “sloppy” repairs in the mutated regions, leading to more mutations. The combination of the two SHM steps jeopardizes genomic stability, and it was thought, up until now, that the risk of genomic instability is avoided mainly due to the occurrence of the first SHM step only in antibody genes.
However, as David Schatz, Professor of immunobiology at Yale, discovered together with his colleagues, AID mutates many other genes in B cells, including genes linked to lymphatic cancer and other malignancies. Moreover, they found that the same DNA repair enzymes recognize mutations in many other (non-antibody) types of genes in the B cells, but fix them in a precise (“high fidelity”) manner.
Studying lymphatic cancer therefore requires understanding of both the first SHM step (the original mutations) and the second SHM step (the repair process). “It now seems likely that anything that compromises the function of these DNA repair processes could lead to widespread mutations and an increased risk of cancer. If the precise, or high fidelity, repair processes break down, this would unleash the full mutagenic potential of the initial mutation, resulting in changes in many important genes,” Professor Schatz said. The researchers believe that this sort of breakdown of the repair processes occurs in the early stages of the B cell tumors’ development.
Another lymphatic cancer research previously covered by TFOT focused on overcoming the blockage of B-cells’ apoptosis (programmed cell death) mechanism. Unblocking this mechanism may allow the cancerous B-cells to regain control of their proliferation.
Yale University‘s press release covering the SHM study is available here.