GENETIC MUTATIONS GIVING FURTHER INSIGHT INTO HEMATOLOGIC MALIGNANCIES, POINTING OUT WHERE ABNORMALITIES ARE WHICH WHICH WILL IMPACT SIGNIFICANTLY RESEARCH FOR THERAPY.

While Multiple Myeloma seems to result from amplification of major pathways with Ubiquitinated molecule persistence being one of the major therapeutic interventions (as a result of proteasome inhibitors), most likely by feedback blockage of major pathways and mitotic check point arrests, Myelodysplasia and Leukemia are going purely NUCLEAR.  SF3B1 mutation now associated with Refractory Anemia with ring Sideroblasts and cases of Chronic lymphocytic leukemia, putw us square and fair into the realm of m-RNA splicing.  The new interest in SETBP1 ties some case of mental retardation to elevated risk of Anemia. (Schinzel-Giedion Syndrome).  But remember, the elevated risk of AML in Down Syndrome-Coincidence or similarity, is the question!

Finding abnormality in the PRPF8 gene in dysplasia and leukemia brings back and re-enforces that splicing abnormality may be a significant driver in these conditions.  These findings cast doubt that researchers pushing drugs treating myeloma in Leukemia treatment  may meet disappointment.  It is another animal all around!

Abnormality in CSMD1 gene (regulator in the complement system) caught our attention. Is this an insight into immunodeficiency in Dysplastic syndrome...?  we will follow-up!

Another gene PPFIA2 is down regulated by Androgen therapy in prostate cancer, if it is significant, can we use this as predictive indicator in a therapeutic strategy?

We can't seriously finish without talking about the RUNX-1: what a major target since differentiation lays here.  But is differentiation a meaningful target?  Remember, allowing these cells to fully mature may lead them to Apoptosis... so let's weigh this one! 

The future is exciting in Research!

POLYUBIQUITINATION

The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins.  To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal.  The anti-proteasomes in effect block this plan.  And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways.   Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth?  Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think?  Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?