[suzierose]

Mitochrondrial respiration and TP53 regulation

by suzierose on Fri Dec 16, 2011 8:50 am

One of the things that has perplexed and flummoxed me about the pathogenesis of multiple myeloma is the medical view that chromosomal changes are indicative of 'advanced disease'. The underlying premise being the universally accepted medical/scientific dogma that chromosomal changes/mutations are rare. Ergo, multiple myeloma patients with negative cytogenetic abnormalities are diagnosed as being in an advanced stage as evidenced by the existence of the rare nature of chromosomal changes.

Yet, when looking at the tests used to judge tumor burden vs. aggressiveness there were inconsistencies I could not correlate.

For example, if the tumor burden is low based on B2 microglobulin of less than 2.5 mcg/ml along with FLC( the new gold standard) of less 200mg/L, how then does a low tumor burden accompany a patient profile with virtually every high risk cytogenetics out there? i.e. MAF, TP53, del 1p, gain 1q, t (14:16)

IF, cytogenetic abnormalities are believed to be an outgrowth of long standing 'advanced disease'? i.e. chromosomal changes are rare events

What could account for a low tumor burden and so many cytogenetic abnormalities?
Shouldn't a low tumor burden be indicative of catching the disease in an early vs. advanced stage, particularly based on FLC outcomes?

So, the question I asked was could cytogenetic abnormalities actually precede vs being the sequelae of multiple myeloma pathogenesis? Could the abnormal cytogenetics actually be independent of the pathogenesis of multiple myeloma itself, i.e. early vs. advanced?

What could account for a low tumor burden and so many cytogenetic abnormalities? Is a low tumor burden 'advanced disease'?

IOW's which came first the chicken or the egg?

These are the inconsistencies & questions, along with DEX power, that kept me awake and scouring the literature.

And then I stumbled across mitochrodrial dysfunction.

I learned that mitochrondria are gatekeepers of genomic stability and that cytogenetic changes found in cancer, ranging from point mutations to gross chromosomal changes can arise following damage to the structure and function of mitcochrondria. This then would be consistent with low tumor burden and numerous cytogentic abnormalities independent of multiple myeloma pathogenesis.

Next, I discovered there was a link between 17p aka the 'big dog' TP53 suppressor gene (that trumps all the others) and mitochrondrial dysfunction.
http://www.jbc.org/content/286/23/20297.abstract
http://www.ncbi.nlm.nih.gov/pubmed/21742773
http://www.pnas.org/content/106/29/11825/F1.expansion

Are cytogenetic changes the result of long standing multiple myeloma disease or could the chromosomal changes been produced by a pathway independent of multiple myeloma..if it is the later is it not possible that newly diagnosed patients, while they remain high risk for cytogenetics, they do not necessarily have 'advanced disease' based on the low tumor burden lab results?

Does low tumor burden impact with high risk cytogenetic profile change median survival?
I suppose it could also be asked if survival is simply not necessarily dependent on multiple myeloma pathogenesis, or the therapies, since the chromosomal changes are independent of it..
Which is back to the chicken and the egg...is the patient dying from something other than multiple myeloma.
After all TP53 is found in over 50% of cancers...so perhaps it is not multiple myeloma that drives median survival?

[Perseverance]

Re: Mitochrondrial respiration and TP53 regulation

by Perseverance on Fri Dec 16, 2011 4:59 pm

I think the answer is that certain chromosomal abnormalities are a distinct disease from low-risk myeloma. As the understanding of the disease biology has increased exponentially, the definition of myeloma has stayed singular rather than diverging into at least two dinstict diseases, as it clearly needs to be defined. For instance, in the same fashion of hogkins and non-hodkins lymphoma, I think Barlogie (GEP70 defined high risk) and non-Barlogie low risk myeloma definitions are in order. So, I think the appropriate inquiry, is not where along the string chromosomal abnormalities arise, but rather which string we are talking about.