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#1 CallMeLucky


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Posted 25 December 2012 - 11:49 PM



12/25/2012  An international team, headed by researchers at the University of California, San Diego School of Medicine, has identified a key enzyme in the reprogramming process that promotes malignant stem cell cloning and the growth of chronic myeloid leukemia (CML), a cancer of the blood and marrow that experts say is increasing in prevalence.

Chronic myeloid leukemia blood cells

The findings are published in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences (PNAS).

Despite the emergence of new therapies, such as tyrosine kinase inhibitors, CML and other leukemias remain problematic because some cancer stem cells avoid destruction and eventually regenerate themselves, a stem cell process known as self-renewal that can result in a return and spread (metastasis) of the disease.

In the PNAS paper, principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at UC San Diego, with colleagues in the United States, Canada and Italy, report that inflammation - long associated with the development of cancer - boosts activity of an enzyme called adenosine deaminase or ADAR1.

Expressed during embryogenesis to help blood cell development, ADAR1 subsequently turns off and is triggered by viral infections where it protects normal hematopoietic stem cells from attack. In leukemia stem cells, however, overexpression of ADAR1 enhances the missplicing of RNA, which leads to greater self-renewal and therapeutic resistance of malignant stem cells.

The findings build upon previous studies by Jamieson and others that elucidate the effects of RNA missplicing and instability. "People normally think about DNA instability in cancer, but in this case, it's how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy."

The described RNA editing process, which occurs in the context of human and other primate specific sequences, also underscores the importance of addressing inflammation as "an essential driver of cancer relapse and therapeutic resistance," Jamieson said. It also presents a new target for future therapies.

"ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors," said Jamieson. "If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning."

CML is a cancer initiated by a mutant gene called BCR-ABL in blood forming stem cells that leads to an expansion of white blood cells and their precursors. It is typically slow-growing and often not diagnosed until its later stages when there can be a sudden, dramatic increase in malignant cells, known as blast crisis. Median age of diagnosis is 66 years; incidence of the disease increases with age. Despite tremendous advances in BCR-ABL tyrosine kinase inhibitor therapies, the majority of patients relapse if therapy is discontinued, in part as a result of dormant cancer stem cell resistance. This work suggests a novel mechanism for overcoming cancer stem cell resistance to therapy that may prevent relapse and progression.

The estimated prevalence of CML in the United States is 70,000 persons with the disease, projected to steadily increase to approximately 181,000 by 2050. CML is initiated by the mutant BCR-ABL gene, but scientists have not yet identified the cause of the mutation.

Date  -  Lab  -  Scale  -  Drug  -  Dosage MG  - PCR
2010/Jul -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 1.2%
2010/Oct -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.25%
2010/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.367%
2011/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.0081%
2011/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2011/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.00084%
2011/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.004%
2012/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Dec -  MSKCC  -  Non-IS  -  Sprycel  - 100 - 0%
2013/Jan -  Quest  -  IS  -  Sprycel  -  50-60-70  - 0%
2013/Mar -  Quest  -  IS  -  Sprycel  -  60-70  - 0%
2013/Apr -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.036%
2013/May -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.046%
2013/Jun -  Genoptix  -  IS  -  Sprycel  - 50 - 0.0239%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0192%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0034%
2013/Oct -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0054%
2014/Jan -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0093%
2014/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.013%
2014/Apr -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0048%
2014/Jul -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2014/Nov -  Genoptix  -  IS  -  Sprycel  - 100 - 0.047%
2014/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0228%
2016/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Dec - Genoptix  -  IS  -  Sprycel  -  100 - 0%


#2 TeddyB


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Posted 26 December 2012 - 04:06 AM

Good reading.

Curcumin should be good for inflammation, so maybe taking 500-1000mg as a daily routine should be in order?

Lets hope they can develop some kind of ADAR1 inhibitor for eradicating those CML stemcells.

By the way, is this related to the article "How close are we to targeting the leukemia stem cell?" found here http://www.bprch.com...081-3/fulltext ?

#3 Tedsey


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Posted 26 December 2012 - 08:44 PM

Thanks for posting.  I have a few questions for anyone out there who could answer.  Although it would be wonderful if blocking the ADAR 1 pathway is successful, sadly, it does not tackle quiescence.  Clearly, I am not the only one thinking this (Teddy).  But, it is going forward, and rather quickly.  That is always good.

1) Are the majority of CML patients really dx in BP?  I thought most are dx in CP.

2) Is it really true that CML is becoming more prevalent?  I wonder why.  Environmental toxins?  More stress in people's lives than ever before?  An increase in human population and its movement around the world?

3) I have read the "inflammation" subject brought up over and over.  What is inflammation exactly?  (Internal/external?  Chicken or egg?) 

4) Besides medication, how does one go about reducing inflammation?  Is it possible?  Cancer patients die even when they meditate and do yoga, etc. to reduce stress.  It must be more complex than just relaxing.   

I feel so very skeptical about the body's ability to heal itself.  Before CML, I did everything we are told by the media, cancer and heart societies as right.  I followed the rules, and I lost.  I see people tempting fate with bad life habits and I get so angry.  I didn't do any of that!!!  And they are cancer and disease-free!  Now, I am more than ever a believer in luck.  Some of us just have more of it than others, and some of us have better health than others, (whether we do something that may destroy it, (ex. smoking, excess weight), or not).  But deep inside, I cannot help that somehow I caused the CML and I am petrified I will give myself another cancer (I think I must be practically 100% inflamed and I don't know what to do besides swallow my TKI every night).  I feel helpless now, like my health went so out of my control.  How did this happen?  I guess if I can believe in the Big Bang, I can try to stomach that mutations just happen.  Very rare, but pretty much, a fact.

Sorry.  I think I am a little depressed tonight.  And despite my toddler biting through her face after a fall and 6 hrs the ER bleeding until they sewed her up, I had a very happy Christmas (we got away lucky and I took my little girl home).  Go figure.  Maybe it is the deflation after the holidays.



#4 Trey


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Posted 26 December 2012 - 09:06 PM

1) You are correct.

2) No. CML patients are becoming more prevalent.  Gee....I wonder why.....  (Pause while Jeopardy music plays in background -- please respond in the form of a question.)  "What is TKI drugs are making them live normal lifespans so there are more of them?"  (Bell chimes signalling correct answer.)  "I'll take Potent Potables for 500".......

3) "Inflammation" at the cellular level is (loosely) a form of ongoing cell stress, irritation, or injury (my definition).

4) Cells don't do yoga. 

Sharts happen. 

Glad your little girl is fine.  You will be fine.

#5 Guest_billronm_*

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Posted 27 December 2012 - 12:52 AM


  Those cells look like my stovetop did after I went on a health food kick and bought fresh beets and cooked them. I'm back to canned beets!             Billie

#6 Trey


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Posted 27 December 2012 - 10:25 AM

By the way, that photo is Blast Phase CML.  Chronic Phase blood looks closer to normal except for quantities of WBCs.

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