A WILD GENE! THE EP 300

Every time we talk about a "wild gene", we get a reaction from our readers.  This is a good sign.  Basically, what we call wild gene is one full of interactions.  We talked about adapter genes which basically direct in one or the other direction of global Metabolism, but we also make sure that readers understand that these adapters can allow a gene to acquire proliferative potential by hooking it to another gene that routinely drives proliferation (such as the gene that pushes Antibody formation).  By all definitions, EP300 is a wild gene.

Another power to this gene is the fact that it leads to Malformation when it is missing:
"Rubinstein-Taybi syndrome.", THROUGH THE MAML1 GENE, THIS GENE IS IN COMPLICITY WITH THE NOTCH1.  And you know how we hold dearly the Notch as an important gene/pathway...

EP300 is involved in all major cancers including Acute Leukemia.  You remember that Acute AML cells have not fully completed differentiation.  EP300 is the master of differentiation and of course will be mutated or altered in bad AML.  So, in a way, it is prognostic!

" Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form."

HOW MANY GENES INTERACT WITH EP300? YOU BE THE JUDGE!

"Interactions"

EP300 has been shown to interact with Mothers against decapentaplegic homolog 7,^[6] MAF,^[7] TSG101,^[8] Peroxisome proliferator-activated receptor alpha,^[9][10] NPAS2,^[11] PAX6,^[12] DDX5,^[13] MYBL2,^[14] Mothers against decapentaplegic homolog 1,^[15][16] Mothers against decapentaplegic homolog 2,^[17][18] Lymphoid enhancer-binding factor 1,^[19] SNIP1,^[20] TRERF1,^[21] STAT3,^[16] EID1,^[22][23] RAR-related orphan receptor alpha,^[24] ELK1,^[25] HIF1A,^[26][27] ING5,^[28] Peroxisome proliferator-activated receptor gamma,^[29][30] SS18,^[31] TCF3,^[32] Zif268,^[33] Estrogen receptor alpha,^[29][34][35] GPS2,^[36] MyoD,^[24][37] YY1,^[38][39] ING4,^[28] PROX1,^[7] CITED1,^[40] HNF1A,^[41] MEF2C,^[37] MEF2D,^[42][43] MAML1,^[44][45] Twist transcription factor,^[46] PTMA,^[47] IRF2,^[48] DTX1,^[49] Flap structure-specific endonuclease 1,^[50] Myocyte-specific enhancer factor 2A,^[51] CDX2,^[12] BRCA1,^[34][52] HNRPU,^[53] STAT6,^[54] CITED2,^{[55][56][57][58]} RELA,^[59][60] TGS1,^[61] CEBPB,^[62] Mdm2,^[63] NCOA6,^[64] NFATC2,^[65] Thyroid hormone receptor alpha,^[51] BCL3,^[66] TFAP2A,^[56] PCNA,^[67] P53^{[68][63][69][70][71]} and TAL1.^{[72]wikipedia"}

SUPPRESSION OF NF-kB IS ONE OF THE DOMINANT EVENT IN ACUTE MYELOID LEUKEMIA,

As we explore the major genes involved in Acute Myeloid leukemia, we quickly realize that the main initiating event is located in the Core binding factors or complex proteins located at the Histone-DNA.  At this level we already uncovered that the nature of molecule interacting and  involved are considerably important, and fundamentally different when you speak about Hematological neoplasm versus solid tumor.
Globally, they appear to be several levels of action:

1.  Nature of components of Histone (H1A, H2A etc..) as cover of DNA. 
2.  Complex involved in Histone remodeling  (H1Ax)
3.  Portion Alpha-subunit of protein complexes attached to the DNA to control its expression, and here we find the RUNX which control Hematologic differentiation
4. Portion of Alpha subunit that actually ensure just clear attachment to DNA so that the Histones do not run in the nuclear  solution.  But be careful in fact most of the time if not always, the place of attachment of histone is not random and varies according to nature of tissue involved.  That is Histones attachment contribute to gene silencing and tissue differentiation.
5. Then there Beta subunits which send tentacles dealing with
    5.1-pure Histone Deacyl transferase activity
    5-2- DNA uncoiling and coiling
    5.3- Interaction with Regulators
    5.4-Interactions with cytoplasmic  signal trasductions (MAPK, FOS/c-JUNK, RAS,PI1K ,VEGF)
    5.5-output back to the cytoplasm to inhibit or activate regulators of signal transduction.  The control of signal transduction pathways is done through enzymes production but through activation of switches (E3, SOS) and through control of Ubiquitination and the MDM2
   5.6- DNA replication controlled through P53, and check-point control molecules.
    5.7-signal to Mitochondria, the Ribosome AND AT C-MYC
  etc. (Transcription factors)
The Centrosome have a DNA attachment portion and an endonucleases portion and some endonucleases find their way to  this area of histone-DNA.

Suffice is to say that in AML, the RUNX is involved to ensure Hematologic differentiation, Many regulators are involved, but suppression of the NF-kB and therefore suppression of the TGF is an significant find!
One now speculate as to why it is so.  AND WITHOUT HESITATION, ONE CONCLUDE THAT IT IS BECAUSE AML DOES NOT NEED TO FORM A MASS!  THE SUPPRESSION OF TGF CAN BE INSUFFICIENT HOWEVER, AND A GRANULOCYTIC SARCOMA IS CREATED BUT THIS IS RARE.

(CLEARLY SOME OF THE CONCEPTS PRESENTED HAVE STILL TO BE FULLY VISITED BY RESEARCHER AND READERS-READ MORE TO ESTABLISH THIS IS SO!)

IT IS INTERESTING TO NOTE THAT WHILE IN THE STRUGGLE IS AT THE RUNX IN AML, IN BLADDER CANCER THE TGF IS IS FULL SWING, DNA REPAIR IS IN FULL SWING, BUT ALSO EVENTS AT THE HISTONE MODULATION AS ALSO IN FULL SWING

The AML discussion continues!

AML-1 mostly corresponds to the alpha subunit of the CBF and contains the RUNX-1 which specializes in hematologic differentiation of the cell, the other portion already contains among other things regulatory or catalytic molecules facilitating many processes of the cell combination with EVI-1 will control signal pathways and growth factors.
This type of AML, or AML in general, appears to be a disease mostly driven by dysregulation of promoters and regulator genes with global suppression of the NK-kB a nd the cyclins/TGF. 
?role of ANDROGEN, interferon and growth factor in EVI-1 positive AML can be raised as a question.  On top of standard induction chemotherapy of course!  This is where Cyclosporine and Antithymocyte Globulin could still have a role (in EVI-1 AML)

One may wonder why TGF is suppressed?  Maybe to stop the cancerous process to form a mass and stay "fluid"?   That is, in granulocytic sarcoma, TGF would be less suppressed?

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)

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!