survival) by inhibiting the apoptosis-causing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer. BCL6: This genes product, Bcl-6, is a repressor of transcription that regulates the expression of other genes which control cell maturation, proliferation, and survival. MYC: This protooncogenes product, Myc, encodes a transcription factor which regulates the expression of other genes whose products stimulate cell proliferation and expansion to extra-nodal tissues. EZH2: This genes product, the EZH2 protein, is a histone-lysine N-methyltransferase. It thereby regulates the expression of other genes which control lymphocyte maturation. MYD88: This genes product is a signal transducing adaptor protein essential for the transduction of interleukin-1 and toll-like receptor signaling pathways. It thereby regulates NF-κB and MAPK/ERK signaling pathways that control cell proliferation and survival. CREBBP: This genes product is a transcriptional coactivator; it activates numerous transcription factors, some of which control cell proliferation. CD79A and CD79B: these genes products are critical components of the B-cell receptor. Mutations in either gene can cause uncontrolled cell activation and proliferation. PAX5: this genes product, Pax-5, is a transcription factor that controls the development, maturation, and survival of B-cells; it also controls expression of the MYC gene in these cells.As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR, JAK-STAT0, MAPK/ERK, B-cell receptor, toll-like receptor, and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors.
In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving the kidneys, adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses. Pathophysiology
Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and tranlocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this diseases development and/or progression. BCL2: This gene is a protooncogene, i.e. a normal gene that can become cancer-causing when mutated or overexpressed. Its product, Bcl-2 protein, regulates cellular apoptosis (i.e.