Wednesday, February 27, 2013

TARGET THERAPY FOR ACUTE MYELOID LEUKEMIA (AML)

FOR THE NEXT FEW DAYS, WE ARE GOING TO JOIN THE DISCUSSION ON DEVELOPMENT OF TARGET THERAPY FOR ACUTE MYELOID LEUKEMIA (AML)
A preliminary review announces very heated discussions and development of new hypotheses that will that may raise eyebrows, but will certainly be an exercise to go through.  But until the current thinking are significantly challenged, we may remain with ARA-C and  Anthracyclines as back bone of our induction treatment.  We will approach this topic deliberately and systematically by first discussing in general the underlying evidences that makes an Acute Leukemia a good prognosis disease. We will then review each good prognosis AML as much as the discussion allows.

GOOD PROGNOSIS AML:

 Favorable group Inv 16, (15,17), (8,21)
 favorable include Inv 16,( 8,21), NPM1, CEBPA and wild type FLT-3

 IN GENERAL,
 These syndromes appear to result from suppression of genes at the Nuclear level. In the cell sometimes various proteins achieving similar or parallel functions sometimes refused to be isolated. so they come together in a large molecule called a complex molecule or a CORE binding Factor. Despite their association, each molecule, like a tentacle or swimming appendices continue to do its specific work.  The Core binding Factor appears to have at least 2 subunits, one grabing on to the DNA and one continuing to do its job.  And by attaching to an area of the gene, it can suppress its expression, while the other side is working on the cover of genes (the Histones).
In fact in those AML were t(8,21) is characteristic, the core binding factor activity act as an histone Deacytylase inhibitor sending suppression effects in the Ribosome, the Telomere, the centrosome, and transcription factors.  In all the good prognosis AML, this is the center of ACTION!
NOW what happen after this irreversible suppression,  please remember our discussion of the Histone Deacetylase on this blog!  This suppression however is not enough to cause Leukemia, a secondary event must happen to cause Leukemia!  Radiation, chemotherapy, Benzene, in AML1-ETO (8,21) AML speculation that some "Ethyl-Nitrosourea" like compound have to strike to induce finally the Leukemic process!

The Molecule attached to the Core Binding Factor determines the type of leukemia you have.  If the Core binding grabs MYH11, you got yourself inversion 16.  If it grabs ETO, you got M2 (8,21).  The point is :

1) Giving Histone deacetylase inhibitor indiscriminately does not make sens if inhibition is there already. we will talk about why it may work sometime.
2) Notice I enumerate a number of stressor (radiation and chemicals) well in the cell stress usually goes to a member of the MAPKcalled c-JUN and the cell try to escape of fight through the NF-kB and these pathways control the Cyclins, TNF and others growth factors.  What happens now ?
Suffice is to say that a group in Indonesia did bone Marrow in Lupus patients who had Cytopenia, they found among other findings, " 50 % hypercellular Marrows, 35% Plasmacytosis, 10% Aplasia, 10% dyserythropoiesis, 5% Myelofibrosis.  Suggesting that Autoimmune/inflammatory process can independently produce Marrow changes suggestive or that could lead to Cutopenias and Leukemia!  This rise the possibility that  REGORAFENIB COULD BE CONSIDERED. (READ ABOUT IT, BEFORE RISING THE EYEBROWS!)

(TO BE CONTINUED)



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