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 About Lymphoma > Molecular pathways and therapeutic targets

Last Update: 04/29/2013


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. 


DNA is like a library of instructions telling cells how to act, which contains thousands of books, called genes. DNA exists in all cells except mature erythrocytes.


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. 


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.


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.


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

About - epigenx.com | ermm.cbcu.cam.ac.uk pdf 
Chromatin Remodeling - Protein fibers called histones that interact with DNA. Drugs that inhibit histone deacetylases, for example, may enable expression of tumor suppressor genes.



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.


 Related articles

Molecular Genetics of Cancer Division - wehi.edu 
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

"Ultimately, this effort will guide patients towards therapies that are tailored for their particular diseases and will identify new molecular targets for therapeutic development."

Molecular & Cellular Treatment Targets


  Prevents programmed cell death
   Enhances metastatic potential 
   Promotes resistance to anticancer therapy
 Indicates poor prognosis in many cancers - Genta

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

  • Molecular Genetics of Cancer Division - wehi.edu

Deregulation of the genetic expression of BCL-6 may lead to lymphoma and promotion of tumor growth.
BCL6 (B-Cell Lymphoma 6)  details - Atlas of Genetics and Cytogenetics in Oncology and Haematology
The BCL-6 Proto-Oncogene: Function in Normal and Malignant B Cells - Hilda Ye, Ph.D
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
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
CASP10 gene
"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] 
  1. Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas. 
    Blood. 2002 Jun 1;99(11):4094-9. 
    PMID: 12010812 - PubMed


Here we will post links to information about genes associated with lymphoma.
Analysis of the Smad2 gene in hematological malignancies.
Leukemia. 1998 Jan;12(1):94-5.
PMID: 9436926 - PubMed
Genetic characteristics (FCGR3A genotype) predict response to Rituxan?
 - Blood 2002 Feb 1 |  PubMed
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
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
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
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

nuclear factor-kappaB
A transcription factor
Nuclear factor-kappaB "plays a major role in viral replication, cell proliferation, and immune response." - PubMed
Hot Papers In Signal Transduction (The Scientist) - By None
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
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
P-53 gene
(tumor suppressor gene)
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.
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
Key cell suicide gene has helpers, MIT team reports - MIT News
Protein Kinase C
transcription factors
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.

Transcription Factors
"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.
Signal Transduction
Proteins that mediate signal transduction include: protein kinase C,  protein tyrosine kinase, and the ras protein - Boik,  Natural Compounds in Cancer Therapy.
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.

Bax, Bak, Mcl-1, anti-Fas

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