Why is chromosome 14 a site of high-risk myeloma genetics?

In a previous lesson, we learned that translocations T414, T1416, and T1420 are linked to a poor prognosis and help classify patients into high-risk groups when these translocations occur alongside chromosome 1 abnormalities. But have you ever wondered why chromosome 14 is such a hot spot for high-risk myeloma genetic translocations? In this lesson, we'll uncover the critical role chromosome 14 plays in our genetic makeup and why these translocations drive aggressive disease. Why is chromosome 14 a site of high-risk myeloma genetics? One of the main roles of a normal plasma cell is to make antibodies. And so when that cell meets a foreign object, it undergoes some changes in its genetic code so that it can recognise that foreign object and kill it off. So let's say it's a pneumonia cell. The plasma cell will undergo some changes to make sure it can kill that pneumonia cell off most effectively. And those changes, the main place those changes occur in a normal cell is on chromosome 14. So essentially, it makes the best fit antibody and it does that on chromosome 14. So it's really then not a surprise that when we think about a myeloma plasma cell, that the area that most often goes wrong is that spot on chromosome 14 because it's programmed to do something anyway. And then what happens in myeloma is it gets hijacked. And so it breaks apart, which is what it should do, but rather than joining itself back together again, which is what it would do if it was fighting a pneumonia infection, it joins, accidentally joins with another chromosome. And that's where the problems start. How do plasma cells make antibodies? The translocations that we see in myeloma come from errors of cutting and pasting DNA that are an integral part of development of plasma cells and B cells. So plasma cells are part of the immune system that have been likened to the snipers of the immune system. Their job is to produce the bullets of the immune system that we call antibodies that normally are directed against invaders to the body, viruses, bugs, and they come out of a type of immune cell that we call B cells. Now B cells, when they decide to become plasma cells, when they decide to become snipers, they need to learn how to make bullets and how to make antibodies. And part of this process involves cutting and pasting of DNA. The cutting and pasting of DNA is not random. It has to happen at specific locations. They often involve chromosome 14 because on chromosome 14, we have genes that instruct the B cell to make antibodies, to make bullets. In other words, the genes for the bullets of the immune system that we call antibodies are on chromosome 14. So if you are a B cell that has decided to become a sniper of the immune system, to become a plasma cell, you need to pay attention to your chromosome 14 because that's where you will find, if you want the prime material to make or to be able to generate bullets of the immune system, to be able to generate antibodies. So chromosome 14 is of prime interest in these cells. They will look there for how to make antibodies. They will need to cut and paste pieces of DNA. And as we were saying in conference, nothing in life is 100%. Mistakes happen. So the part of chromosome 4, for example, in the 414 translocation, should have never come next to the chromosome 14 part. It's an error. It's a mistake. It's a random event that rarely happens, but when it happens, it gives the myeloma cell superpowers, the powers to divide faster, the powers to not die when it reaches the end of its lifespan. So that sets the stage for what we eventually will diagnose in the clinic as myeloma. So chromosome 14 is a prime location that encodes for parts of antibodies. So a plasma cell has a lot of interest in chromosome 14. It will try to work on chromosome 14, but if a mistake places another oncogene, a cancer gene, right next to chromosome 14, which by the way is a very powerful region, then that error could lead to one of the translocations, the 1114 translocation, the 414 translocation, and so on, that we see as initiating events in myeloma.