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

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)

Leukemia inhibitory factor

From Wikipedia, the free encyclopedia

Leukemia inhibitory factor
PDB rendering based on 1LKI.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	LIF; CDF; DIA; HILDA; MLPLI
External IDs	OMIM: 159540 MGI: 96787 HomoloGene: 1734 GeneCards: LIF Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3976	16878
Ensembl	ENSG00000128342	ENSMUSG00000034394
UniProt	P15018	P09056
RefSeq (mRNA)	NM_001257135.1	NM_001039537.1
RefSeq (protein)	NP_001244064.1	NP_001034626.1
Location (UCSC)	Chr 22: 30.64 – 30.64 Mb	Chr 11: 4.26 – 4.27 Mb
PubMed search	[1]	[2]

Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.
Function LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on bone metabolism, cachexia, neural development, embryogenesis and inflammation. p53 regulated LIF has been shown to facilitate implantation in the mouse model and possibly in humans.^[1] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.^[2]

Binding/activation

LIF binds to the specific LIF receptor (LIFR-α) which forms a heterodimer with a specific subunit common to all members of that family of receptors, the GP130 signal transducing subunit. This leads to activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen activated protein kinase) cascades.^{[citation needed]}

Expression

LIF is normally expressed in the trophectoderm of the developing embryo, with its receptor LIFR expressed throughout the inner cell mass. As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF.

Use in stem cell culture

Removal of LIF pushes stem cells toward differentiation, but they retain their proliferative potential or pluripotency. Therefore LIF is used in mouse embryonic stem cell culture. It is necessary to maintain the stem cells in an undifferentiated state, however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene Nanog.
LIF is not required for culture of human embryonic stem cells.^{[3][4]
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These comments from Wikepedia introduce our discussion today,
first of all, patient with leukemia have their cells stopped at various stage of differentiation
meaning some are stopped at baby stage, some at teenager stage, some at adult stage. And at each stage, the leukemia takes a different Name, agressiveness and prognosis. In General, the younger the stage the bad/worse the prognosis. So there is a benefit to HELP ALONG THE CELL TO GROWTH, IT ACTUALLY IS HELPFUL FOR THE CELL TO MATURE SO THAT THE TUMOR GETS A GOOD OR BETTER PROGNOSIS.
AS A MATTER OF FACT, THE MORE MATURE THE CELL BECOMES, THE LESS LIKELY IT WILL DIVIDE REDUCING THE LOAD OF THE TUMOR.  THE MORE MATURE IT GETS, THE MORE LIKELY IT WILL GET OLD AND DIE OF A NATURAL DEATH. 
ON THE OTHER END HOWEVER, THE MORE LIKELY IT MATURES, THE MORE LIKELY IT MAY COMPLETE OR PERFORM ITS NATURAL FUNCTION. SO IF ITS FUNCTION WAS TO BE ABLE TO SPREAD, THE MATURE CELL CAN SPREAD FASTER.  THAT'S WHY SCIENTISTS ARE REPORTING THAT AN INHIBITOR TO THIS LIF  MAY STOP THE SPREAD OF CANCER.  THE MD ANDERSON HAS BEEN WORKING ON THIS AND HAVE REPORTED SOME SUCCESS! THE FIGHT IS ON!}