Friday, March 1, 2013

PART III AML
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WE WERE SAYING:

Should CBF activity lead to MYCN amplification directly or through overexpression of miR17-92 (with ribosomal location), at least 8 consequences results:

1.Overexpression of CDK4  (Cyclin dependent kinase 4) which phosphorylate RB-1 and stops the cell cycle in G-1.  Remember p16ink 4a is its inhibitor (Melanoma).   Therefore MYCN stops proliferation!  That's why its a good prognostic factor!

2.  Overexpression of RSG2 ( G protein regulator) mostly with inhibitory membrane and submembrane activity effects affecting cell division  as well as angiogenesis, again good for you!

3.Overexpression of MDM2, a ubiquitination ligase of P53.  In Leukemia, proliferation will be exacerbated by this action (not so good for us! but inhibitors could prove good target therapy) 
   
4. Overexpression of TERT, This is where the AML cells insure longevity by exacerbating  or mutating the the Telomerase Reverse Transcriptase, insuring the stability of DNA repeats or prolonging the tail that protect chromosome-This is not food for us.  Association with Hypoxia induced factor point more likely to preparation to handle stress and possibly tissue invasion that occur sometimes with leukemia.

5.Overexpression/Mutation of RNF11 This gene seems to code for a Ligase that allows protein-protein interaction.  Ubiquitination and attachment to membrane protein may be compromised limiting full deployment of NF-kB pathways.  it may account for  susceptibility to infection as cellular immunity would be severely compromised.  Sometime frame shift Mutation is all it takes when miRNA are targeted.
(we will look into the role of DUMPS and CD-38 as they pertain to RNF11)
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6.  Interaction with - E2F1, a transcripton factor,  through inhibtion of Rb-1, controls proliferation, 

                             - ODC-1, RATE limiting enzyme at the base of the amplification system and therefore at the center on Oncogenesis, you knock down the OC-1, good bye amplification since mutation here removes the rate limiting effects  (sensitive target!)  (Ornithin Carboxylase 1)
                        
                              -PPM1G
Roni Koren at al wrote:
"PP2A1 is one of the major protein serine/threonine phosphatases in the cell, which plays a role in several cellular processes, including metabolism, transcription, RNA splicing, translation, cell cycle progression, morphogenesis, signal transduction, development, and transformation (1, 2)."

PPM1 mutation is the soul of Dedifferentiation of Myeloid cells, and possible increase of migration.
"Mutations in PPM1, which methylates protein phosphatase 2A, and target of rapamycin (TOR1) were characterized further. Deletion of PPM1 almost completely suppressed the rapid lethality and substantially suppressed glucose wasting during starvation for leucine or uracil. Suppression by a deletion of TOR1 was less complete."
Viktor  Boer at al reported. This hinted that PPM1 Mutation presence may mitigate MTOR inhibition effect.

These 3 alterations involve Chromosome 2
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7.   Over-expression of INHBE, NACA, SHMT2

-INHBE Better described here
 

UniProtKB/Swiss-Prot: INHBE_HUMAN, P58166

Function: Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary
gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary
hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin
secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition.
Inhibins appear to oppose the functions of activins


-NACA
 " NAC binds to nascent proteins as they emerge from the ribosome, blocking interaction with the signal recognition particle (SRP) and preventing mistranslocation to the endoplasmic reticulum. However, nascent proteins with an exposed signal peptide will not be bound by the encoded protein, enabling them to bind the SRP and enter the secretory pathway. This protein has been determined to be an IgE autoantigen in atopic dermatitis patients. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]"

-SHMT2
' Serine hydroxymethyltransferase (SHMT) is an enzyme (EC 2.1.2.1) which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine (retro-aldol cleavage) and tetrahydrofolate to 5,10-methylenetetrahydrofolate (hydrolysis).[1] This reaction provides the largest part of the one-carbon units available to the cell.[2]' wikipedia



 Globally, leukemic cells seems to stay dedifferentiated  by shielding themselves away from mesenchymal transformation and away from the effect of growth factors.  the SHMT2 challenge us to redefine the role or not of anti-folate.  Here we know where one carbon-Unit are coming from.  We also have here futher evidence that the NF-kB is completely dysrgulated or suppressed in Leukemia.  DKK3 SUPPRESSION PUT SUPPRESSION OF THE WNT SIGNAL TRANDUCTION CENTER TO THE LEUKEMIC PROCESS.  DEREPRESSION HERE IS NEEDED.




8.  Suppression of DKK3, ESR1, TGF beta 

DKK3 
"is involved in embryonic development through its interactions with the Wnt signaling pathway. The expression of this gene is decreased in a variety of cancer cell lines and it may function as a tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding the same protein.[2]"wikipedia 

DKK3 SUPPRESSION PUT SUPPRESSION OF THE WNT SIGNAL TRANDUCTION CENTER TO THE LEUKEMIC PROCESS.  DEREPRESSION HERE IS NEEDED.





ESR 1

DECREASE OF ESTROGEN 
ALPHA RECEPTOR IS USED HERE TO RESTRAIN DIFFERENTIATION AND ALLOW GROWTH UNDER STRESSFUL CONDITION, AND CONTROL AGING.

TGF1 IS ALSO SUPPRESSED TO AVOID GROWTH AND DIFFERENTIATION


GLOBALLY IT APPEARS THAT DIFFERENTIATION THROUGH MEK, PITUITARY HORMONES, GROWTH FACTOR (TGF beta), INSULIN, COULD HAVE A SHOT AT MINIMIZING ACUTE LEUKEMIA BASED ON INTUITIVE DATA PRESENTED ABOVE!  IS LEUKEMIA RATES LOW IN DIABETICS WHO ARE TAKING INSULIN?
PROF OF CONCEPT NEEDED AT CRBCM.  INCREASING OR PROTECTING WNT SIGNALING MAY BE ANOTHER FIGHTING APPROACH. 
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