Methylation focus on CLL

I have recently returned from Clinical Trial monitoring at OSU and was granted a tour of OSU research labs. This tour was synchronistic as I have been interested in how epigenetics affects CLL. I got to talk with some research assistants in the forefront of studying the mechanism of methylation. Knowledge of the methylome will unlock new methods of treating CLL with less toxicity and hopefully cures. Methylation is a buzz word for our patient community so I wanted to let you folks know to keep your antennae up as research into the methylome is now a hot topic yielding important findings for many cancers with a paper recently published by Spain's Barcelona group using CLL as a cancer model. I had an inspiring talk with a former member of Spain's Barcelona group Dr. Pilar Dominguez at the LRF Chicago Conference who is now researching methylation at Weill Cornell in NY.

While I am on a steep learning curve to absorb the implications of what methylation research may do for us I can tell you that that understanding methylation in CLL will be extremely important for a cure to be realized. To date no one knows what causes our CLL. The Barcelona group has revealed some complex methylation changes as the B cells transform from naive cells to somatically mutated soldiers of our immune system. sciencedirect.com/science/a...

Ohio State Univ. Medical Center has a prominent researcher, Dr. Christopher C. Oakes author and co-author for many papers on methylation with a focus on CLL. Stay tuned. cancerdiscovery.aacrjournal...

WWW

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  • I've taken a few MOOCs (Massively Open Online Courses) on epigenetics. In particular WEHI's

    coursera.org/learn/epigenetics

    In a nutshell, methylation is the addition of a methyl molecule to DNA at particular places on a stretch of DNA. It is usually quite normal, and absolutely necessary for proper DNA expression - either preventing that stretch from being translated or encouraging it. It's part of what makes each cell into the unique tissues we have as the embryo develops. Since all cells with a nucleus have the same DNA, the epigenetic marks are what makes a skin cell into skin, and a bone cell into bone. But things can and do go wrong, especially with cancer.

    en.wikipedia.org/wiki/Methy...

    But I've always wondered why there is such focus on methylation, when acetylation, posphorylation, and other markers are also part of epigenetics.

    en.wikipedia.org/wiki/Epige...

    I suppose it has to do with the fact that methylation is the most common type of marker, can be tested more easily at the moment, and is a little bit better understood, Plus the buzzword marketing.

    I would caution people that there are web sites that attempt to report on methylation status based on over the counter genetic tests, like 23andMe or Ancestry.com. They then may try to sell you vitamins or herbs that supposedly compensate for the methylATION genes they detect, not the methylATED genes. There are genes that produce the enzymes that read or make the methylation changes, and OTC genetic tests sample them. But over the counter genetic tests report only on a fraction of your actual DNA, and do not include any status on which genes are actually methylated or in which tissues.

    The theory behind which vitamins or herbs might be helpful is also quite sketchy, if not entirely doubtful. This is why there are so few legitimate methylation treatments approved for medical use outside of research:

    Use of Epigenetic Drugs in Disease: An Overview - ncbi.nlm.nih.gov/pmc/articl...

    blogs.biomedcentral.com/on-...

    Often, the argument is that "simple vitamins can cure X, so big pharma is not interested". The actual issue is that one wants to get the treatment to the right cells. If your mutation(s) are due to a lack of methylation on one gene, and too much on another, will the vitamin make the disease better or worse?

    DNA methylation in cancer: too much, but also too little - nature.com/onc/journal/v21/...

  • Hi SeymourB,

    What is intriguing is not so much what is observed by current aberrant methylation so far but what has caused the healthy, just-right amount of methylation that is needed to carry out necessary gene function to go awry. Methylation is a dynamic mechanism much more so than the other markers currently tested.

    By examining methylation patterns it is thought to bring us closer to pinpointing where in the pathway of B cell maturation a cell becomes cancerous. Methylation patterns may also play a distinctive role in why some monoclonal B cells remain indolent and non destructive to a patient's health or longevity without treatment interventions.

    Hyper-methylation in naive B cells are linked to poor prognosis in CLL but too often markers like this are not definitive guides to optimize therapy choice.

    I would welcome any questions you might have that I can put to researchers if the opportunity arises.

    WWW

  • Thanks, ThreeWs!

    I'm curious if there is a theory that methylation itself is responsible for mutations. Or does a change in methylation "simply" make an existing mutation worse?

    Mutations in genetics are usually focused on indels (insertions and deletions of DNA) and translocations (entire chunks of a chromosome moving to a different place in the same or another chromosome). These mutations usually happen when DNA is replicated when the cell divides. Are scientists now thinking that methylation problems cause replication problems?

    Or is there a possibility that methylation problems cause genes that are normally silent if B-cell development to express themselves, and either increase growth rate, or prevent apoptosis?

    I'm also interested in finding out what labs in the U.S. (university or elsewhere) are doing the methylation testing for CLL patients.

  • Hi Seymour,

    Your questions are spot on and I was trying to find a video I missed filed to direct your attention to linking methylation and acetylation. I suspect that link is important to part of your inquiry.

    The Transcriptome is a huge focus for where normal cell division becomes corrupted but that does not answer genesis questions or what I refer to as the "Nested Daruma Doll" dilemma. Given all the feedback loops, checks and balances to keep our cells normally functioning the recognition of any aberrant chemical/biological structure that becomes established like hypo/hyper-methylation may speak to and answer up-stream levels of greater malfunction & consequences but what initiated the methyl groups to produce hyper or hypo methylation to begin with?

    The search for answering cancer genesis should eventually lead to early non-toxic interventions. (CRSPR??) In the meantime knowing the state of what is dysfunctional may help us choose a preferred therapy.

    I may be in contact with some knowledgeable scientists before year's end that can help us clear the fog at least to some degree. Stay tuned -

    WWW

  • Boy am I a dummy. I'm glad you guys get it. Whatever you guys said, i hope and pray it will be instrumental towards a cure.

    Jeff

  • With well over a million epigenetic changes so far discouvered by the Barcelona CLL group... sorting that out is going to take some time...

    International Cancer Genome Consortium...scroll down to CLL...

    icgc.org

    Also

    icgc.org/icgc/cgp/64/530/826

    ~chris

  • That's my impression, too, Chris.

    This is why I'm curious about labs that want to actually sample us real patients. It would provide the necessary raw data to help sort through the possibilities faster.

    I would love to take a holiday in Spain - which I wish I could afford!. I've even been taking Spanish language classes lately. But I wonder if there are scientists in the U.S. that are also participating somehow. I have read other studies where patients have had their blood drawn in the U.S., and then sent to Europe for other diseases.

    =seymour=

  • Seymour,

    You will be pleased to know that at OSU I keep the phlebotomy vampires well supplied with extra blood that I suspect are at the foundation for methylation research and neo-antigen vaccine development. The gal that drew my blood even remarked on the high tube count. It gives me an excuse to chow down on a large burger when I leave the hospital and walk into town. I am negotiating to get one of the cryo-storage containers named after me;-)

    With Dr. Pilar Dominguez from the Barcelona group doing research at Weill Cornell in NY I suspect The same is going on there as well. Pilar said the work in Spain is excellent but the funding is down.

    WWW

  • Good phlebotomists are way underappreciated. We should know.

    So will it be the WWW Memorial Cryo Container, or something that flows more trippingly on the tongue?

    I look forward to the Spanish results.

    I'm reading Mukherjee's Gene: An Intimate History right now. I highly recommend it. It's aimed at the non-scientist. I'm only 150 pages into it, and so far, the plot has Watson and Crick borrowing X-ray photos that Rosalind Franklin had taken of a string of DNA. He goes into their personalities, and allegations that the photos were stolen.

    He wrote an earlier book that I really enjoyed as well, The Emperor of All Maladies: A Biography of Cancer.

    =seymour=

  • Perception takes up a lion's share of our reality so the difficulties of making sense of mega-data in methylation research is dependent on tools such as super computers and machine learning.

    An appropriate analogy to the agreed on mountain of data generated by study of the methylome is the sequencing effort for the human genome which plodded along so slowly for so long. At the point where only 1% of genome sequencing had been accomplished many very bright scientists & pundits predicted that it would take a hundred years or more to achieve a 100%. Ray Kurzweil, scientist/visionary/futurist predicted very accurately that most of the work had been done at 1% and very soon the job would be completed. He was right. It was his comment on the process of evolving technological evolution that enabled his accurate prediction. "Law of accelerating returns"

    I can tell you that critical CpGs have been identified in number of cancers to include CLL that are thought to be fundamental to understanding methylation's role in cancer. OSU is using more CpGs than what the Barcelona group identified and that is expected until a standard is reached.

    We have already witnessed an acceleration of novel drugs based on signaling pathway research so I am not one to be pessimistic about how long we might see encouraging results emerge in the methylation arena.

    WWW

  • Wayne,

    I am encouraged that you are encouraged to put it mildly.

    Jeff

  • Justasheet1 -

    You are by no means a dummy. I am an amateur, myself. Professionals have trouble keeping pace with all this - new lingo, new possibilities.

    I think for most of us, this is like listening 2 car enthusiasts talking about engine innards, while we simply want a ride into town.

    It's definitely stuff that is on the horizon, and ultimately, one wants to hear "You should get this test, or that treatment."

    But, there is an alternative medicine market, and I did want to bring up the fact that "methylation" as a buzz word is being marketed to people, who may feel desperate.

    =seymour=

  • Well said!

  • I would be the first to thank Seymour to the alert on Con-artists using methylation as a gimmick to push pseudo medicine. I came across one prominent con on Youtube (Ben Lynch) who might seem to be very knowledgeable to the unwary. Just say NO!

    WWW

  • Hi Jeff,

    I am a poster boy for one who is capable of gaining a conceptual grasp of cancer biology and how drugs work without benefit of any academic training. I have no deep technical knowledge and I would argue that it is not necessary for the patient community to feel that they must have degrees or specialized training to be functionally literate in their disease. In fact I would argue it is vital for optimal care that patients be educated to be effectively involved in their cancer management.

    Do you or other patients really need to know about methylation research at this point? No but it is a fascinating thrust into one of the most important and little understood areas of biological functioning, that being epigenetics.

    I am not naive enough to think revelations made from methylation study will translate into clinical action anytime soon but I like to keep ahead of the curve. Had I not tried to understand ZAP-70, a signaling marker, I might never have picked Ibrutinib out of a number of therapy options presented to me after disastrous failures on FR and RTX. If I had not questioned and demanded an explanation for why I nearly died on FR & RTX and blindly followed the recommendation of a Heme/Onc to try Ofatumumab I would likely not have survived to write this.

    If I can become knowledgeable you can too. It is only a matter of will and desire. I am not judging either way - only to free you to the option.

    WWW

  • Ah Wayne, if it was only that easy. Will and desire can't overcome low IQ's but I appreciate your IQ very much. I'm glad you and others are looking after the flock and not the wolves.

    Jeff

  • Thanks for heads up, need to lie down now and absorb so many new words! :-)

  • Thank you guys,

    Good to know that research is going on that like Jeff I cannot get a grip on. Methylation, now why does that make me think of down and outs, sleeping in cardboard boxes.😳😀😀🤔

    Sorry guys bit of humour does not mean I don't appreciate the sharing, thank you. I think I get it.

    Bubnjay1

  • In humor there is always a bit of truth. Aberrant methylation like crystal meth to a human produces a destructive addiction of sorts in the gene so affected. It is pushing the metaphor a bit far but ....

    WWW

  • Fascinating, and a little over my head at the moment. I think it's cool that they gave you a tour of the lab. I also go to OSU and I literally saw just Dr. Byrd for the first time since I started my trial in June. My friends and family don't understand why this doesn't bother me. I tell them it's far more important that he sees new patients or hangs out in the lab working to figure out the next standard of care or cure for all of us, and from how excited he was last week, I do think they are on the verge of something groundbreaking.

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