CLL Support Association
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A not-so-dumb question about IGHV clonal evolution

As part of a discussion a week ago titled "Warning this may be a dumb question" ( healthunlocked.com/cllsuppo... ) DMary wrote the following: "A helpful private message told me that IgVH mutation doesn't change and suggested I look at the older posts on this. I did. I was confused in thinking that clonal evolution (the emergence of the strongest CLL cells following treatment) would effect the IgVH mutation status. I still don't understand why it doesn't, but I have a limited ability to get my mind around the workings of blood cells, blood cancers and DNA."

I sent DMary the private message she was referring to and it turns out that I was wrong. In looking through the 2017 ASH abstracts today I came across the one below that addresses her question about clonal evolution of the IGHV region. I THINK that it reports that using the standard Sanger sequencing technique clonal evolution isn't observed, and since that is the traditional way of assessing the DNA sequence of the IGHV region, the prevailing thought has been that there is no "evolution" in that region ie no increase or decrease in mutation status over time. It now appears that her intuition was correct...if everything else is subject to clonal evolution why not the IGHV region? Using a different sequencing technique, one that sequences mixed batches of DNA, the IGHV sequence of every cell in a sample can be determined and there is evidence that the sequence of the IGHV region can change over time. I think that we will have to wait for a peer-reviewed paper to find out the details or significance.

Abstract 54 IGHV-D-J Repertoire Analysis Obtained By High-Throughput Sequencing of CD5+ B-Cells in CLL Patients: Prognostic Markers and Disease Development Implications

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In summary, we document that CLL clones diversify in vivo, accumulating IGHV-D-J mutations that generate clonal complexity and subclonal expansion not previously appreciated. This, occurring in both U-CLL and M-CLL, directly correlates with time to first treatment, and may serve as an indicator of DNA aberrations occurring genome-wide (“genetic instability”) likely reflecting the action of the DNA mutator, activation-induced deaminase that can also lead to genomic changes outside V-gene loci. Finally, the common presence of secondary expanded clones, unrelated to the CLL clone, also has prognostic significance and may give insight into the development of CLL.

ash.confex.com/ash/2017/web...

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Thanks for your diligent research and follow through Gardening-Girl. Like so many things in CLL I guess that this is something to watch, but not to worry over.

I do appreciate your posts. I know my understanding of these things is bare bones and the subject is quite complex. You've been a real help.

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Thank you for the update, which just goes to show that research into CLL is continually progressing. Personally, I've found that learning the medical science of CLL has made me aware of how little we really know about the intricacy of our immune system and how CLL arises and develops. It also increases my concern for those that trust general oncologists to manage and treat their CLL; if the complexity of CLL is typical for all cancers, how can a generalist ever hope to keep across developments in all solid and blood cancers?

(I've also edited your post so the link to DMary's not so dump question works - the HealthUnlocked site can't identify web links unless there are spaces between the link and adjacent non-space characters.)

Neil

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Thanks Neil.

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