In all the pathology, there is no disease that makes so much sense than Chronic Lymphocytic Leukemia disease I will beg to venture. Our understanding of this disease has grown so rapidly that what is left to discover is probably not as much as one may think. What is needed today is a reorganization of what we know and minute details particularly at the Nuclear levels. The disease affects about 15000 people, and kills about a third of our people who happen to have gone in a wrong path because of a genetic failure particularly in our way of managing infections and cellular death. And along these paths, there are laws that need to be followed, and any failure of following these laws leads to these dangerous disease called CLL.
The first observation to remember following this theory is that there is no clear environmental disaster that can induce CLL directly unless people exposed have a genetic failure in their cellular death control! CLL is the only type of leukemia not noted after the Chernobyl Nuclear Reactor incident and there no correlation with CLL with other chemicals or Benzene exposures!
Infections however have a demonstrated activity in CLL occurrence. Scientists will tell you tha disturbances of the NF-KB, NFAT and STATs are commonly found in this disease. With the Infections, one can quickly conclude that Cytokines and growth factors are and must be involved and they are (ie. disturbance at IL4). (Adenopathies'swelling is a result of cytokine activity!) These are common occurrences, why is it that CLL is not why spread?
1.For CLL to occur, you got to have disturbance in the law against cellular death.
The first evidence for this is the fact that mainly and or only disturbance in DAPK 1 (Death receptor) has been clearly and convincingly demonstrated to be found in familial CLL. There is a law of nature that says, "to fight infection, the cell must close the door to programmed death, But Apoptosis must happen when certain circumstances are met". In CLL, This last portion of the law must not be met! The B cell involved, most likely a memory cell, has gotten rid of genes that fulfill this last portion of the law! They forget the notion of death. It is not by mistake that sometime up to 98% of CLL cells have deletion of 13q14 which removes the regulator of Bcl-2 (miR16). And it is not by mistake that there is an expansion of of Bcl-2, bak , Mcl-1 and XIAP reported in the literature. (and try to find bax or caspases, they are profoundly "suppressively" disturbed) All are a consequence of relatively total suppression of Apoptosis. Now wonder why the cells of CLL are mature non dying cells!
2.The law of desensitization.
When an antigen, or any stimulant persists at a receptor, natural laws will kick in to engage desensitization. Nor desensitization has been normally described as decrease in receptors. The reality is just a it more complex. As a matter of facts, decreasing receptors which are proteins assumes decreasing gene or gene expression but the reality can be more severe! Gene could be mutated or silenced, or fully deleted. Sometimes the full arm containing the gene could be lost. There are many deletions in CLL and silencing of promoters (ID4, SFRP family and even DAPK) is notoriously common. Desensitization can start at receptors, G proteins to miRs and Chromosome arms removal! This happens for proteins involve in regulations of cytokines, regulators of many involved genes, and hell, even Glycogene regulation is deranged in the process! The law of desensitization is violated big time here! In presence of chronic stimulation, even The IgVh region is Mutated! (a strong prognosis in CLL)
Abruptly you find yourself facing the inadequacy of current Biomarkers for CLL. But things are coming your way with a vengeance and soon! The CRBCM is following...!
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