The Science of B-Cells

This one is for the inquiring minds among us, not really an update. We are so blessed to have some really smart - and interesting! - friends. One of them, Tammy, shared some more insights with me about the proteins I was referencing yesterday: BCL-2, BCL-6, and MYC. Tammy went to University of Richmond with Kristen and has a PhD in Biochemistry and Molecular and Cell Biology from Harvard University. One of her career focuses is communicating science to the general public, which based on how she explained this, I'd say she's pretty good at it!

I really appreciated her taking the time to explain some more details about how these proteins and their genetic mutations cause them to grow into lymphoma tumors. I'm constantly amazed at how or bodies work, both at a microbiological level and how all of the systems work together to sustain life in an rather hostile environment. I thought you might also appreciate it, so I copied it below with her permission.

3D Rendering of a B-Cell

Credit: Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

How Myc, Bcl-2, and Bcl-6 Function in a Cell

Hundreds (or more) proteins work together to make even the tiniest event in a cell happen, and signals from inside or outside the cell cause chemical changes to these proteins that in turn change their functions to change what events can occur. Most relevant to cancer are the events of cell division (to make more cells) and cell death. There’s a constant battle between proteins that cause a cell to NOT divide and proteins that tell a cell to divide. There’s another battle between proteins that tell the cell to NOT die and proteins that tell the cell to die. All the markers you listed fall into the category of proteins that make the cell divide or proteins that tell the cell not to die. Where “genetics” comes in: The “recipe” to make each protein is a gene (or more than one gene) in the DNA. When you think about results of a genetic test, we’re talking about checking to see if these recipes are correct or not. Sometimes, the actual protein-encoding gene (the recipe) is perfectly fine, but other areas of the DNA that tell the cell how much or how often to express the gene (go through the steps to make a protein using that recipe) is messed up, so the cell makes too much or too little. You can think of it like googling for a recipe for cookies and having one over-represented due to Google’s search algorithms - the recipe is available to everyone, but maybe it shouldn’t be the top hit). Everyone’s DNA contains genes for Myc, Bcl-2, and Bcl-6. What’s special about your tumor cells is that they’re making these proteins when they shouldn’t be (I’m not sure what the genetic tests are measuring directly, but that’s what the end result is). How these proteins work and how their over-expression may affect response to treatment: Myc: Myc’s job is to turn on genes (cause gene expression so the proteins get made) for proteins that directly cause cell division. It’s a regulator of sorts. If your cells are making too much Myc, it may be more difficult to get them to stop dividing (one of the main goals of chemotherapy) because Myc is trying to tell your cells to keep dividing all the time. Myc is really common in lots of cancers, though, and most of the drugs in your chemo cocktail work by damaging the DNA (which should increase signals telling cells to die and at a minimum prevent the cell from copying the DNA, which is a prerequisite for cell division) or preventing the process of cell division, so even if Myc is telling them to divide they won’t be able to. Bcl-6: this one is also a regulator of sorts. the “Bcl” just stands for B cell lymphoma, so any of these Bcl mutations are definitely common in your general type of cancer. I’m not as familiar with the exact function, but it is involved in allowing B cells to very quickly reproduce when they come in contact with their target antigen (so they produce antibodies). In that way its function is a bit similar to Myc. The other thing that’s interesting about Bcl-6 is its role in how the cell tolerates damage to DNA. B cells are pretty unique because they are some of the few cells in the body that actually CHANGE their DNA and not just gene expression and protein chemistry. The reason for this is to allow your body to produce so many unique antibodies to so many different invaders. They only alter their genes for the antibodies, not all the other genes in your cells. The process of changing the DNA involves cutting it up a bit, which usually would cause the cell to pause and potentially trigger the cell to kill itself due to too much damage. I’m reading that Bcl-6 is somehow involved in allowing the cell to tolerate this DNA damage, though I have no idea how. This part may actually be the most relevant to chemotherapy response because so many of the drugs work by damaging DNA. However, before that makes you panic, the WAY your chemo cocktail damages DNA is mostly through different types of DNA damage, so it might not be relevant at all. Bcl-2: this one isn’t involved so much in telling the cell whether or not to divide, it’s involved in telling the cell not to die. Bcl-2 is important normally because you don’t want all your cells killing themselves at the slightest sign of damage (which would start to activate proteins that tell the cell to die). However, when there’s too much Bcl-2, cells can’t die even when they’re supposed to. It’s all a balance. This is relevant for response to treatment because the chemotherapy drugs need to not only make the cells stop dividing, but also kill them. Otherwise, they’ll stop dividing but could eventually start again down the road. Your chemo cocktail causes cells to get stuck through so many different methods, though, that Bcl-2 shouldn’t make it ineffective, it just ups the challenge a bit. From my understanding, in a LOT of lymphomas, Myc starts causing cell division when cells shouldn’t divide, which starts activating proteins that tell the cell to die. By having extra Bcl-2, these cells are able to override these signals to die, so they divide out of control (cancer!). This combo may make the cancer a little harder to treat, but there are so many other factors involved that I wouldn’t worry much. The correlative data for DLBCL may not apply at all in your specific circumstances. Lymphomas in general tend to be easier to treat than a lot of cancer, and you’re in a great hospital with lots of experts. Hopefully this explanation clarifies things. My actual field of expertise is DNA replication and repair, which generally extends into the cell cycle (how cells divide/don’t divide) and cancer biology. I’m less familiar with the more statistical side of things - for example, the information says that specific DNA changes that affect these three proteins causes decreased response to chemotherapy in DLBCL, but it doesn’t say why on a biological level. My explanations give my personal best guess for why, but linking these markers to their biological function and whether the statistical correlations to treatment response are applicable to other cancers, even in the same family of cancers, is still more or less a crapshoot.