29 replies to this topic

[CallMeLucky]

To clarify my stand on vaccine, it was not based on this debate about healthy people with BCR-ABL.  I was thinking more about the trials that are underway for the DNA vaccine being run at University of Southhampton

http://community.lls.org/thread/9249

[cherylannes]

And Interestingly enough, Dr. Rezvani work was one of the articles I posted earlier. ......

Functional leukemia-associated antigen-specific memory CD8⁺ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation

Katayoun Rezvani, Matthias Grube, Jason M. Brenchley,Giuseppe Sconocchia, Hiroshi Fujiwara, David A. Price,Emma Gostick, Ko Yamada, Jan Melenhorst, Richard Childs,Nancy Hensel, Daniel C. Douek, and A. John Barrett

[PhilB]

Unfortunately there is a big difference between finding T cells which are reactive to BCR-ABL and demonstarting that those T cells can actually do anything concrete about the disease.

Don't get me wrong, if the Southampton trial is still recruiting if and when I qualify then I will try to sign up for up, even though I don't have much faith in it's success, but I see it as no downside to me and adding to the body of knowledge so I won't be particularly bothered whether I'm in the treated group or the control.  There may be some hope of the vaccines helping with clearing out minimal residual disease in those with a really deep TKI response, but I repeat that I have yet to see any evidence that immune response on its own could prevent the development of full blown CML when the translocation occurs in a self-replicating stem cell.

Phil

[valiantchong]

Hi,

I was wondering on detection of BCR-ABL gene embeded in the DNA of all of the cells in a typical CML patient using DNA PCR. I am confused here, as it is detected in some stoped TKIs patients, if the BRC-ABL gene is embeded in the DNA due to genetic error, from what I know these BCR-ABL will bound to multiply, due to the biological fact that DNA must multiply during cells mitosis.

Correct me if I understand wrongly, does BCR-ABL gene found in the DNA of all the cells or some cells only, as it will make a big different. If the DNA error found in all of the cells, then CMLers will not have hope of curing unless the fault is reversible. Any study that show the error is reversible ?

If the detection is found on some minor cells, than we may have hope of curing thru the immune system which could kill the faulty cells. As from what I know from biological science, if some error is embeded in the gene, it will multiply. Unless apotosis occured in these faulty cells or NK cell will take care of it.

I was wondering if normal healthy person found any faulty gene in their DNA using DNA PCR test. As from the reports it showed using the in normal RT-PCR and not DNA PCR in stop TKIs patients.

Any study on the DNA of all of the stem cells of a CMLers compare to a healthy individual ?

[PhilB]

Hi VC,

I'm afraid no-one has ever done a study looking at the DNA of ALL the stem cells in an individual as the first step in the test would be to put the patient in a liquidiser.   The translocation is most definitely in some rather than all of the cells.  To be in all of the cells it would need to have been in the original sperm or egg and in that case I presume it's unlikely the foetus would even survive to term.  This isn't something anyone needs to worry about though, as the chances of it happening are astronomically small.  Even if your blood is 99.999% Ph+ve the rest of your body won't be as the muation doesn't give any competitive advantage to cells in other lines and so the mutant doesn't spread anywhere but in the blood and marrow.

You can think of the cells that go on to produce blood cells as a pyramid.  At the top you have a small number of stem cells that can create just about anything - including exact copies of themselevs.  Go down a few layers on the pyramid and you have cells specialised into the myeloid line, but which are still producing stem cells and can still copy themselves.  Go down further still and you have many more stem cells which can churn out functioning blood cells, but can't make copies of themselves.  At the bottom of the pyramid you have the multitudes of functional blood cells that keep us alive, but can't reproduce - the worker bees.

The 9:22 translocation could happen pretty much anywhere in the pryamid, but if it happens far enough down that the cell can't reproduce itself then it will only last as long as that cell lives and is unlikely to be able to create enough offspring to ever produce a clinical sympton.  A few of the blocks at the bottom of the pyramid will be Ph+, (and may be detectable) but the great majority of the pyramid will remain normal - and our normal regulatory processes will be quite capable of adjusting for the increased production of the Ph+ cells so CML will never develop.

To develop CML the translocation has to happen high up in the pyramid in a cell that can self replicate and therefore be able to pretty well take over its own layer rather than just those beneath it.

Phil

[valiantchong]

HI,

That means only a small % of stem cells has DNA faulty, the issue still exist. If the error not reversible, then the DNA bound to multiply, unlless cell apotosis or NK cell take care of this. As base on the stem cell geometrical progression rate of multiplication 1,2,4,16,32,64,128,256,512,1024,...etc.....and it is occuring daily.,,.It will still doom for CMLer, the faulty stem cell will multiply so quickly without medication. I was wondering the how a patient who stop the TKIs could survive more than 2 years without progression some can survive till 5 yrs, and still DNA detected BCR-ABL ? What is the biological suppression mechanism for these stem cell ? Or the stem cell could be in "quiesent" stage for more than 2 yrs ? Any study on quiesant stage of these CM stem cell, how long it could stay quiesant ?

From my biological knowledge, DNA is the define the cell functionality, if BCR-ABL code is embeded in the faulty DNA steam cells, CML will definately progress in time. Which means progression is inevitable for all patients. Correct me if I am wrong, I hope I am not sounding negative here... I wish there is a cure too.... 

[PhilB]

Hi VC,

It's a lot more complicated than your simple geometric progression.  That model works for things like bacteria where every cell and every reproduction is the same.  What we have is a much more complex model with the vast majority of reproductions  producing a daughter cell different to the parent.  You have to look separately at 'downstream' reproduction vs 'sideways' reproduction and remember that only the relatively very small number of cells at the top of the pile are capable of the latter.

If you have an unregulated stem cell which is not capable of self-reproduction ie it can only engage in downstream reproduction then you effectively have a closed system.  It produces daughter cells as fast as it can, but can only produce so many before it reaches the end of its lifespan and dies.  The same is true for the daughters and only a few steps down the chain you get to the worker blood cells which can't reproduce at all and so that's the end of the progression.  For the life of that top cell you have a gushing tap, but it's a tap that can only produce so much and fortunately for us it's gushing into an ocean. (I personally believe that this is what accounts for any presence of BCRABL in 'healthy' patients).  In order for CML to progress you need the original translocation in a high enough level cell to create sufficient numbers of long-enough-lived 'taps' to change the level of the ocean.  Reproduction up at these higher levels is a much slower process making CML a slowly progressing disease, but if unchecked it will proress like a plum tree taking over a garden.

[Trey]

VC,

You might want to read this:

http://community.lls.org/message/24653

[CallMeLucky]

VC - I can appreciate where you are coming from and I understand your passion about this.  I think it would help though if you didn't use terms like "we're doomed" and "progression is inevitable".  I know you are speaking in the context of not taking drugs for the rest of our lives, but there is a sensitivity here that we should try to be respectful of.  I'm not trying to censor what you are saying, and we all recognize the seriousness of our disease and the implications and potential issues.  I just think, given the highly successful treatment options we have, that we are not doomed and that progression is not inevitable.  Again, I realize you are talking about if one were to stop taking meds, but it comes across a bit harsh.  I know you said you are not trying to be negative.  Again, I am not looking censor and if that is the way you truly wish to convey your message, then that is your right, but I just wanted to comment on it.  I think it is important for people reading this, especially newly diagnosed, or those who don't understand the technical nature of what is being discussed, to be fully aware that we are not all doomed.  We have very good odds of surviving for many years.  We all want a cure, but until that happens I think it is important to acknowledge that the prognosis is very good for most of us with medication.

All the best

[cherylannes]

Hello Valiantchong,

This is a difficult question to answer because there are different ideas of what mechanisms allow the disease to persist.  Recently we are hearing that the researchers are agreeing that there is a finite group of leukemic stem cells (LSC).  If this finite group of LSC's can be eliminated then the disease cannot be reconstituted.  One theory that some researchers are kicking around is why is it that these patients in Europe (100 of them now) have been able to stop TKI for several years (there is five year data now) and still show detectable levels of BCR ABL using DNA PCR, yet not relapse.  In fact, these levels are detectable at some times and not detectable at other times.  This gives rise to the question of whether the last LSC has to be eradicated, some experts say no, most however say yes, just to be sure.

Quite sure that this will generate some additional harsh dialogues, but for what it is worth, there are some links below to some of the published work in this area...

Targeting LSC:
Article in Science daily: http://www.scienceda...00517132842.htm

More on that work here:
http://www.cell.com/...switch=standard

Tessa Holyoake's work on quiescent stem cells:
http://bloodjournal..../105/5/1862.pdf
http://www.springerl...47g056674g6544/
www.cmlsociety.org/Tackling%20resistance%20in%20Chronic%20Myeloid%20Leukemia.doc

http://ash.confex.co...Paper32184.html