Despite the absence of a universal answer for all patients, we do know enough about lymphocyte biology to make some educated inferences. More often than not, I feel compelled to ask the question, “why not me?”
I am constantly in awe of the unbelievable sophistication of the human body. Our genome contains six billion base pairs encompassing over thirty thousand genes across forty six chromosomes – in every cell. If you were to line them up end to end, they would stretch several feet long yet they get packaged into a tiny nucleus. Somehow those six billion base pairs need to be faithfully copied with no errors every time a cell divides. For a B cell this may be thousands of replications.
I saw one paper that estimated that human bone marrow stem cells acquire about ten mutations per decade of life. That is an such an amazingly low error rate that it should affirm your faith in evolution or God depending on your leaning. The fact that life can persist at all is more remarkable to me than the observation that it can break down from time to time.
B lymphocytes however have a number of molecular behaviors that increase the risk of genomic malfunction. B lymphocytes make antibodies (aka B cell receptor / BCR). You make antibodies to fight of bacteria, viruses, and all manner of germs. The mechanism that gives us unlimited antibody diversity involves very deliberate damage to DNA – sometimes with cancerous consequences.
Despite having six billion base pairs, that is not nearly enough to “hardwire” every antibody we may ever need into our genome. Instead, our antibodies are built in a more modular way. We have five types of heavy chains, two types of light chains and every antibody pick one of each. Furthermore, each heavy or light chain has a number of choices for the “variable” region that gets attached to the “D” and “J” regions to create the “VDJ” re-arrangement. At this point, I’ve already lost track of how many possible combinations there are. When it comes to antibody creation, it is like a huge game of Mr. Potato Head.
Each time your B cell takes one “v” region and attaches it to a “d” and then a “j” region, it has to deliberately break the DNA and have it come back together in a different place. That is biologically like trying to jump out of an airplane and land in your swimming pool. Unfortunately that process is sloppy at times – perhaps more amazing is that it ever works at all. Many lymphomas are recognized for having pieces of chromosomes come together wrong called translocations (such as t 4:14, t11:14, or t14:18). If you notice that chromosome 14 seems to keep showing up, that is because it is the chromosome where most parts of the b cell receptor heavy chain are encoded. Sometimes that break and re-attach process comes down in the wrong place near important proteins like Myc, Cyclin D-1, and BCL-2 that cause these cells to take on cancerous behavior (Burikitt’s, Mantle Cell, Follicular respectively).
Even though that process should give us hundreds of antibodies, we need other processes to create antibody diversity enough for life on planet earth. Not surprisingly, there is another diversity mechanism that can run amuck known as “somatichypermutation.” This process takes a perfectly well constructed antibody and starts adding in random mutations. This is key to helping us generate the virtually unlimited number of antibodies necessary. Unfortunately we can find evidence that these deliberate mutations are not always confined to the “variable” regions of antibodies. In fact we can find them sprinkled throughout the genome and sometimes they turn on key proteins like BCL-6, CD79, A20, etc. In CLL we even look for evidence of this process to classify our patients as “mutated” or “unmutated” as it confers a different prognosis between the two.
If you took those two processes alone I think it would probably be enough to explain a lot of cases of lymphoma – but wait there is more.
Abnormal b-cell receptor (BCR) activation appears to be an enormously important event that plays out across many b cell malignancies and possibly explains the fantastic clinical activity of drugs like ibrutinib, CAL-101 (GS-1101) and the like. Different lymphoid cancers get there by different ways. Diffuse large B cell lymphoma occasionally has a mutation in CD79 that locks the BCR into an active state. Other DLBCL’s have mutations in CARD-11 which is farther downstream in the signaling pathway, but activates a key inflammatory complex called Nf-kB. Some cases of CLL may have abnormalities in their “variable” region that trick the cell intothinking it has identified the germ it is supposed to destroy and thereforesends off growth signals to the cell. In follicular lymphoma antibodies may recognize abnormal sugar molecules on each other and get turned on etc. Marginal zone lymphoma sometimes regresses when you treat the stomach or viral infection it is trying to fight off. In Hodgkin’s lymphoma, a viral protein encoded by Epstein-Barr virus (LMP-2) can actually mimic the BCR. That observation was whatled me to hypothesize that inhibiting BCR might be a good idea – way back in2006 before many others had ever thought of the idea.
The theme is that something turns on the BCR in many of these diseases and that gives off growth signals that can lead to cancer. It also explains why some of our most exciting research drugs are ones that turn off that signal.
None of this explains though why some of these things run in families. Occasionally you will find a single family with five cases of CLL. The odds of that happening by chance are a lot worse than your chance of winning the powerball jackpot with one ticket.
One of my favorite researchers / colleagues Dr. JenniferBrown at Dana Farber in Boston is studying this with some of the most powerful technology available. She has identified several families where a shared genetic abnormality explains the occurrence of lymphoid cancer in each of the family members. One interesting example is the loss of a gene called DLEU7 (deleted in leukemia #7). I find this fascinating because that is buried in the middle of chromosome 13q – the most common geneticabnormality in spontaneous CLL. It really points to an area of significant biology for future therapeutic intervention. If you introduce the 13q abnormality into lab mice you will find that they get a variety of lymphomas and CLL.
Finally, there are environmental considerations such as being a meat packer, exposure to pesticides, exposure to certain viruses, etc. This is where science gets a little hard to pin down as it is subject to a lot of forms of bias.
So doc – why did I get my cancer? If “all of the above” was a test choice – that would be my answer. Genomic instability of lymphocytes, a rogue B cell receptor, bad genes, something you were exposed to…
As genomic sequencing gets cheap enough to become a routine clinical test, we may be able to profile an individual cancer for the various hallmarks above and give a more precise answer – but for now, I still have to shrug my shoulders and admit that, “I don’t know.”