About
Lymphoma > Molecular pathways and therapeutic targets Last
Update: 08/03/2004
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LymphoChip
| Molecular & Cellular Treatment Targets Here
we will post information about research into gene expressions that
underlie lymphatic malignancies. We will also post information about
specific genes that have been identified, as well as potential new
treatments that target these genes.
Understanding the basic concepts of DNA
and genes is not difficult and it can help you to appreciate current
directions in clinical research.
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DNA
is like a library which contains thousands of books, called genes.
DNA exists in all cells except mature erythrocytes.
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Genes contain
the instructions or recipe for the creation or expression of
unique proteins that carry out functions, such as start dividing,
or die now.
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Oncogenes
are mutated and/or overexpressed versions of normal genes
that can cause a cell to lose growth restraints, fail to
differentiate to a normal cell, or prevent the cell from
initiating the programmed cell death process called apoptosis. Some
oncogenes turn on other genes that promote cancer.
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It is thought that multiple gene
mutations lead to cancer, and that additional mutations
accumulate over time and in probably as an adaptation to some standard treatments.
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DNA methylation - is a hallmark of
cancer. Specifically, it is the addition of a methyl group to specific
cytosines (the components of DNA) that regulates gene activity.
One analogy for methylation is that of a car
with an ignition that is filled with a glue (methyl). The
ignition (the gene) cannot be turned off so the car runs continuously.
So if sv40 causes methylation of key genes, it can alter the
behavior of the infected cells in aberrant (bad) ways. So
malignant behavior (loss of growth control or inability to die) can
be caused by damaged genes (i.e., translocations) and also by
methylation which changes which genes are turned on or off.
Hypermethylation can cause oncogenes to produce
proteins that cause malignant behavior.
Hypomethylation can quiet genes that normally
suppress cancer (tumor suppressor genes).
In this modification, methyl (CH3) groups are
added to the DNA of specific genes within the cell at specific
sites. These groups sit on the DNA and block certain proteins from
binding. In this way, the DNA methylation could be stopping the cell
from operating normally, Teitell said.
"By silencing cellular genes, this type of
modification is damaging a cell's ability to sense its environment
and may be causing it to grow uncontrollably," Teitell said. - unisci.com
Chromatin Remodeling - Protein fibers called
histones that interact with DNA. Drugs that inhibit histone
deacetylases, for example, may enable expression of tumor suppressor
genes.
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| Targeted
therapeutics may be designed to offset the over
expression of oncogenes by drugs that directly target the
these genes, or indirectly by targeting the pathways or signaling that sustain
the malignant expression of genes. |
* * UNDER CONSTRUCTION * *
Links
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Molecular Genetics of Cancer Division - wehi.edu
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Molecular mechanisms of transcriptional
control of bcl-2 and c-myc in follicular and transformed
lymphoma. Cancer Res. 2001 Jul 1;61(13):5202-6. PMID: 11431360
- PubMed
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LymphoChip
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"Ultimately, this effort will guide patients towards
therapies that are tailored for their particular diseases and will
identify new molecular targets for therapeutic development."
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Molecular
& Cellular Treatment Targets
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bcl-2
gene
Prevents programmed cell death
Enhances metastatic potential
Promotes resistance to anticancer therapy
Indicates
poor prognosis in many cancers - Genta
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Bcl-2 is activated as a consequence of
the t(14;18) chromosomal translocation in human follicular lymphomas. When
activated, it blocks cell death and makes the malignant cell resistant to
treatment.
"Bcl-2
acts through a unique mechanism. Prior to the discovery of the
bcl-2 gene, oncogenes were believed to act by inducing uncontrolled
cellular proliferation. In contrast, the bcl-2 gene product was
found to promote survival of cancer cells by slowing or preventing
cell death. Recognition of this novel mechanism resulted in the
establishment of a new oncogene class." - Genta
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Molecular Genetics of Cancer Division -
wehi.edu
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bcl-6
gene
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Deregulation
of the genetic expression of BCL-6 may lead to lymphoma and promotion
of tumor growth.
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The BCL-6 Proto-Oncogene: Function in Normal and Malignant B
Cells - Hilda Ye,
Ph.D
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Significance of rearrangement of the BCL6 gene in B-cell
lymphoid neoplasms.
Leuk Lymphoma. 1997 Sep;27(1-2):53-63. Review. PMID: 9373196 - PubMed
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Internal deletions within the BCL6 gene in B-cell
non-Hodgkin's lymphoma. Leuk Lymphoma. 2000 Aug;38(5-6):505-12.
Review. PMID: 10953971 -
PubMed
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CASP10 gene
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"A
recent report described that inherited CASP10 gene mutations underlie
defective lymphocyte and dendritic cell apoptosis in autoimmune
lymphoproliferative syndrome (ALPS). In this study, to explore the
possibility that mutation of this gene might be involved in the
development of non-Hodgkin lymphoma (NHL), we have analyzed the entire
coding region and all splice sites of the CASP10 gene for the
detection of somatic mutations in 117 human NHLs."
[1]
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Inactivating mutations of CASP10 gene in non-Hodgkin
lymphomas.
Blood. 2002 Jun 1;99(11):4094-9.
PMID: 12010812 - PubMed
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miscellaneous
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Here
we will post links to information about genes associated with
lymphoma.
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Analysis of the Smad2 gene in hematological malignancies.
Leukemia. 1998 Jan;12(1):94-5.
PMID: 9436926 - PubMed
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Genetic
characteristics (FCGR3A genotype) predict response to Rituxan?
- Blood
2002 Feb 1 | PubMed
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Molecular mechanisms of transcriptional control of bcl-2 and
c-myc in follicular and transformed lymphoma.
Cancer Res. 2001 Jul 1;61(13):5202-6.
PMID: 11431360 - PubMed
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Establishment and comprehensive analysis of a new human
transformed follicular lymphoma B cell line, Tat-1.
Leukemia. 2002 Feb;16(2):276-83.
PMID: 11840295 - PubMed
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Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes
from transforming growth factor-beta -induced growth inhibition
and apoptosis.
J Biol Chem. 2000 Dec 8;275(49):38363-70.
PMID: 10995749 - PubMed
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my-c
gene
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Deregulation
of the genetic expression of my-c may lead to lymphoma and promotion
of tumor growth.
"The researchers found that mutations which
activate another oncogene, myc, are particularly potent for
converting a cell carrying a bcl-2 mutation cell into a
lymphoma. The myc gene promotes cell division. Thus the
combination of a growth-promoting mutation (myc) and an
apoptosis-inhibiting mutation (bcl-2 ) is a potent recipe for
cancer." Source:- wehi.edu.au
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nuclear factor-kappaB
(NF-kappaB)
A transcription factor
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Nuclear
factor-kappaB "plays a major role in viral replication, cell
proliferation, and immune response." - PubMed
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Hot Papers In Signal Transduction (The Scientist) - By None
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Antiproliferative effects of IFN-alpha correlate with the
downregulation of nuclear factor-kappa B in human Burkitt lymphoma
Daudi cells. J Interferon Cytokine Res. 2001 Jul;21(7):523-8. PMID:
11506747 - PubMed
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Constitutive nuclear factor kappaB activity is required for
survival of activated B cell-like diffuse large B cell lymphoma
cells. J Exp Med. 2001 Dec 17;194(12):1861-74. PMID: 11748286 - PubMed
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P-53 gene
(tumor suppressor gene)
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The
P-53 gene when properly functioning prevents cells from becoming malignant
by inducing apoptosis, or cellular suicide. When damage occurs to this
gene, or if it under expressed, a cell can maintain it's malignant
behavior, such as prolonged life despite the presence of genetic
damage in the cell.
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Prognostic significance of Ki-67 nuclear
proliferative antigen, bcl-2 protein, and p53 expression in
follicular and diffuse large B-cell lymphoma.
Med Oncol. 2001;18(1):15-22.
PMID: 11778965 - PubMed
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Key cell suicide gene has helpers, MIT team
reports - MIT
News
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Protein Kinase C
transcription factors
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Protein
Kinase C is a group of at least 12 related enzymes that helps to relay
signals thru the cell. It's thought that a wide range of procancer
events (within the cell) rely on abnormally high *signal
transduction.* It's also thought that inhibiting these excessive
signals can slow down the growth or induce apoptosis (cell death) in
cancer cells.
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Transcription Factors
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"Transcription
factors bind to the regulatory portion of a gene and directly serve to
initiate gene transcription. In this way, they have final control over
production of all proteins within a cell, and therefore control much
of the cell's behavior." - Boik, Natural Compounds in Cancer
Therapy.
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Signal Transduction
Proteins that mediate signal transduction include:
protein kinase C, protein tyrosine kinase, and the ras protein -
Boik, Natural Compounds in Cancer Therapy.
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Cells
are not simple. They have extremely intricate machinery that
governs how they behave, reproduce, or die. All these activities
are executed by so-called gene-protein expressions which require
chemical signaling. One part of this signaling process is called
*signal transduction* -- the relaying of signals (ie. grow now signal)
to various parts of the cell.
Protein Kinase C is a group of at least 12 related enzymes that helps
to relay signals thru the cell. It's thought that a wide range of
procancer events (within the cell) rely on abnormally high *signal
transduction.* It's also thought that inhibiting these excessive
signals can slow down the growth or induce apoptosis (cell death) in
cancer cells.
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Bax, Bak, Mcl-1, anti-Fas
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Under construction |
