you may have detected that Mutations at the NOTCH appears to be associated with diseases that not only
are refractory and bent to resist, but also has a "consensus" to progress no matter what!
This is seen with Leukemia, brain tumors,pancreatic cancers, melanoma.
we strongly believe that disturbance at the NOTCH are the reason for the "foolish" mission of cancers to resist no matter what, and to succeed this mission, the NOTCH has to skirt Apoptotic measures! Mutations at the NOTCH have to involve or block all Apoptosis procedures in order to induce an acute leukemia, and for a "consensus", it has to imprint the message through epigenetic events.
When the NOTCH fails to block all apoptotic phenomena, a Myelodysplasia Occurs.
Remember Myelodysplasia most of the time involve Deletion of Chromosome 7 (where the NOTCH was discovered"NOTCH1 was first described as an oncogene by virtue of its involvement in the t(7;9)translocation found in the subset of patients with T cell Acute Lymphoblastic Leukemia" (Clurman). In Acute Leukemia...the where the NOTCH1 was noted there is "impaired differentiation and ENHANCED SELF RENEWAL" the author adds. The enhanced self renew is not only prolong survival but a successful shut down of Apoptosis venues. If the cancerous cell does not shut down successfully the Apoptotic trap, what you get is a Myelodysplasia. "Accelerated apoptosis is the hallmark of early MDS, which explain the paradoxical finding of Normal or Hypercellular marrow in most patients. The malignant clone has an inherent susceptibility to apoptotic cell death" (Alan List et al) But as the epigenetic NOTCH activity continues, the resulting disturbances associated with high level of Cytokines and growth factor results in cellular "autodestructions" of receptors ( a desensitization mechanisms). At the NOTCH which is involved in T cell differentiation, "direct T cell suppression akin to Aplastic Anemia" (List).
This also explain why epigenetic events point to susceptibility to
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