So now for more on 13q:
In cases of CLL where the 13q region is missing, there is variability with regards to just how much is actually gone. You can have the MDR (minimally deleted region), CDR (commonly deleted region) which can occur in the type I deletions, or you can have a huge chunk of DNA gone that eliminates a specific gene called Rb (important tumor suppressor) in which case you have a type II deletion.
If we look at the MDR, we already talked about the miRNA's in the prior post. In humans, the miRNA's are completely embedded in another RNA transcript known as a "sterile transcript." I would love to know what this "sterile transcript" actually does - but so far, nobody has figured it out. It is known as DLEU2 (deleted in leukemia 2). We know from other literature that these "sterile transcripts" do have a regulatory role on certain proteins etc. we just don't know much about this one.
A savvy group of researchers (article linked in prior post) was able to make two different strains of mice. One which just lacks the miRNA's and another which lacks both the miRNA's as well as DLEU2. If you do nothing to the mice except watch them over time, the group lacking the miRNA's gets monoclonal B cell lymphocytosis, some CLL, and some NHL. Interestingly the group that lacks DLEU2 gets more CLL, NHL, and even some diffuse large B cell lymphoma. In summary, the double deletion (miRNA and DLEU2) is more aggressive than just the miRNA.
They did some further experiments and showed that if you take a mouses B cells with these abnormalities and give them a growth stimulus, they start growing faster, and grow longer than normal B cells. Some of these "cell cycle" genes that are affected are classically known to be cancer related - including one of my favorite proteins CHK1 (more to follow when we talk about 11q deletions).
Just a little farther ways out the 13q chromosome lies the DLEU7 gene (different than DLEU2). Instead of being a "sterile transcript" DLEU7 is responsible for actually for the synthesis of a specific protein. This protein has a regulatory role in signaling through a surface molecule known as the BAFF (B cell activating factor) system.
BAFF is interesting to me because it is clearly an important cytokine (aka: micro hormone) in CLL. In fact there are several BAFF inhibitor drugs out there, even one that has been approved in lupus. That drug is locked up in a "custody battle" between two big pharma companies. I've tried to get it for research studies but I don't see that happening soon. There are other anti BAFF drugs out there and I think we will get a readout as to their efficacy in CLL at some point.
One of my research buddies, Jennifer Brown at MGH in Boston has been studying familial CLL and she has identified a family where all the affected family members have a lost both copies of their DLEU7 gene - very interesting.
If you have a really big chunk of DNA missing from chromosome 13q14 (ie. type II deletion), you knock out a copy of the RB gene. RB (aka retinoblastoma - a gene identified as the key driver of an uncommon eye tumor in kids) is a gene that plays a role analogous to p53 in some ways. It is a critical determinant as to whether a cell proceeds through cell cycle or gets halted and may even directly interact with p53 (the key molecule altered in 17p deletions). It appears that having RB deleted adversly affects prognosis.
So in this small area, you have several different molecules that all cooperate to form CLL. This is a pretty power packed part of the genome as far as B cell biology is concerned. Furthermore, it helps us understand ways to go after the fundamental biology of CLL instead of just throwing chemo at the problem.
Next, we will talk about how we test for it currently and what the limitations are of our current testing