View source for Germinal center B-cell like diffuse large B-cell lymphoma

{{Short description|Type of cancer}}
[[Gene expression profiling]] has revealed that '''[[diffuse large B-cell lymphoma]]''' ([[DLBCL]]) is composed of at least 3 different sub-groups, each having distinct [[carcinogenesis|oncogenic]] mechanisms that respond to therapies in different ways. '''Germinal Center B-Cell like (GCB) DLBCLs''' appear to arise from normal [[germinal center]] [[B cell]]s, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation.<ref name="Lenz">{{cite journal |last1=Lenz |first1=G. |last2=Wright |first2=G. W. |last3=Emre |first3=N. C. T. |last4=Kohlhammer |first4=H. |last5=Dave |first5=S. S. |last6=Davis |first6=R. E. |last7=Carty |first7=S. |last8=Lam |first8=L. T. |last9=Shaffer |first9=A. L. |last10=Xiao |first10=W. |last11=Powell |first11=J. |last12=Rosenwald |first12=A. |last13=Ott |first13=G. |last14=Muller-Hermelink |first14=H. K. |last15=Gascoyne |first15=R. D. |last16=Connors |first16=J. M. |last17=Campo |first17=E. |last18=Jaffe |first18=E. S. |last19=Delabie |first19=J. |last20=Smeland |first20=E. B. |last21=Rimsza |first21=L. M. |last22=Fisher |first22=R. I. |last23=Weisenburger |first23=D. D. |last24=Chan |first24=W. C. |last25=Staudt |first25=L. M. |title=Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=36 |pages=13520–5 |year=2008 |pmid=18765795 |pmc=2533222 |doi=10.1073/pnas.0804295105|bibcode=2008PNAS..10513520L |display-authors=8 |doi-access=free }}</ref>  The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.<ref name="Stoudt">Staudt, Louis M. [http://ccr.cancer.gov/staff/staff.asp?profileid=5780] {{Webarchive|url=https://web.archive.org/web/20110727145513/http://ccr.cancer.gov/staff/staff.asp?profileid=5780 |date=2011-07-27 }}, "Center for Cancer Research, Dr. Stoudt Description of Research", Updated 2/20/2009, accessed 1/28/2011</ref>{{Unreliable medical source|date=February 2011}}
==Genetics==
A gene translocation between chromosome 14 (containing the antibody heavy chain locus) and chromosome 18 (containing the BCL-2 locus) is present in 45% of GCB DLBCLs but has never been found in ABC DLBCLs.<ref name="Stoudt" />  This T(14,18) translocation places the [[BCL-2]] gene close to the heavy chain gene enhancer and results in the overexpression of the Bcl-2 protein.  Bcl-2 proteins prevent the activation of the caspases that lead to programmed cell death (apoptosis).<ref name="Kimball">Kimball, John W. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BCL-2.html] {{Webarchive|url=https://web.archive.org/web/20101221200307/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BCL-2.html |date=2010-12-21 }}, "Kimball's Biology Pages, BCL-2", accessed 1/29/2011</ref>{{Self-published inline|date=February 2011}}
Activation of the nuclear factor kappa-light-chain-enhancer of activated B-cells ([[NF-κB]]) pathway is found only in ABC DLBCLs and not GCB DLBCLs.<ref name="Stoudt" />
GCB DLBCL shows amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN but these events have not been found in ABC DLBCL<ref name="Lenz"/>
==Normal B-cell maturation process==
B-cells form in the bone marrow and undergo gene rearrangement in order to develop B-cell receptors (BCRs) that bind to a specific antigen.  Once activated by an antigen, B-cells proliferate and further differentiate into plasma cells and memory B-cells.<ref name="Shaffer">{{cite journal |last1=Shaffer |first1=A. L. |last2=Rosenwald |first2=Andreas |last3=Staudt |first3=Louis M. |title=Decision making in the immune system: Lymphoid Malignancies: the dark side of B-cell differentiation |journal=Nature Reviews Immunology |volume=2 |issue=12 |pages=920–32 |year=2002 |pmid=12461565 |doi=10.1038/nri953|s2cid=33328229 }}</ref> B-cells that have not encountered an antigen are called naive B cells. When naïve B-cells encounter an antigen, one of the pathways that they can follow is through the germinal center environment. B-cells within the germinal center proliferate and undergo immunoglobulin somatic hypermutation (SHM) of IgV region genes to revise their antigen receptors.  The rearranging of genes makes the cells capable of generating antibodies with a higher or lower affinity to the specified antigen.  [[Follicular dendritic cells]] and T cells help to select the B-cells that have a high affinity to the antigen for further differentiation into plasma cells and memory cells.  A large fraction of germinal center B-cells acquire somatic mutations that prohibit antigen binding and these undergo apoptosis.<ref name="Klein">{{cite journal |last1=Klein |first1=U. |last2=Tu |first2=Y |last3=Stolovitzky |first3=GA |last4=Keller |first4=JL |last5=Haddad Jr |first5=J |last6=Miljkovic |first6=V |last7=Cattoretti |first7=G |last8=Califano |first8=A |last9=Dalla-Favera |first9=R |title=Transcriptional analysis of the B cell germinal center reaction |journal=Proceedings of the National Academy of Sciences |volume=100 |issue=5 |pages=2639–44 |year=2003 |pmid=12604779 |pmc=151393 |doi=10.1073/pnas.0437996100 |bibcode=2003PNAS..100.2639K |doi-access=free }}</ref>
==Pathophysiology==
Two oncogenic mechanisms that appear to be active in GCB DLBCL are the prevention of apoptosis and the blocking of terminal differentiation.
===Preventing apoptosis===
Normal germinal center B-cells appear to be poised for apoptosis unless they are selected to progress to the next stage of differentiation.  Most normal germinal center B-cells express low levels of anti-apoptotic proteins such as Bcl-2.<ref name="Shaffer"/>  In GBC DLBCLs, the T(14,18) translocation can result in an increase of the Bcl-2 protein, which may reduce the number of cells that undergo apoptosis.{{citation needed|date=March 2021}}
===Blocking differentiation===
Blocking the differentiation of germinal center B cells is dangerous because the cells are programmed to divide rapidly at this stage.  The SHM that occurs in the germinal center can also target non-immunoglobulin loci and may be responsible for translocation of the BCL-6 gene. BCL-6 genes are involved in several cell processes that can affect the ability of the B-cell to differentiate and proliferate.  BCL-6 genes produce BCL-6 proteins. These proteins work with other transcription factors (BLIMP1, PAX5, XBP1) to form a regulatory circuit that controls the progression of germinal center B cells to plasma cells.  BCL-6 proteins repress genes involved in terminal differentiation and promote proliferation by blocking expression of a cell-cycle inhibitor (p27KIP1). BCL-6 is also an inhibitor of cellular senescence. Cellular senescence is a programmed response that prevents a cell from dividing after some number of cell divisions.<ref name="Shaffer"/>
==Treatment==
DLBCL patients are at higher risk when they relapse early after R-CHOP chemotherapy and have a poor response to second-line rituximab-containing treatments even when these regimens involve high-dose therapy and autologous stem cell transplant.<ref name="Flowers">{{cite journal |last1=Flowers |first1=C. R. |last2=Sinha |first2=R. |last3=Vose |first3=J. M. |title=Improving Outcomes for Patients with Diffuse Large B-Cell Lymphoma |journal=CA: A Cancer Journal for Clinicians |volume=60 |issue=6 |pages=393–408 |year=2010 |pmid=21030533 |doi=10.3322/caac.20087|s2cid=35745203 |doi-access=free }}</ref>  Approximately half of DLBCL patients develop CHOP-resistant cells. A study of DLBCL cell lines indicated that 14-3-3ζ proteins may play a role in mediating resistance of DLBCL cells to CHOP. 14-3-3 proteins exert anti-apoptotic activity by interfering with the function of BH3-only proteins and has been validated as a potential molecular target for anticancer therapeutic development in other types of cancers.<ref name="Maxwell">{{cite journal |last1=Maxwell |first1=Steve A. |last2=Li |first2=Zenggang |last3=Jaya |first3=David |last4=Ballard |first4=Scott |last5=Ferrell |first5=Jay |last6=Fu |first6=Haian |title=14-3-3ζ Mediates Resistance of Diffuse Large B Cell Lymphoma to an Anthracycline-based Chemotherapeutic Regimen |journal=Journal of Biological Chemistry |volume=284 |issue=33 |pages=22379–89 |year=2009 |pmid=19525224 |pmc=2755960 |doi=10.1074/jbc.M109.022418|doi-access=free }}</ref>
===Monoclonal antibodies===
Monoclonal antibodies are made by injecting human cancer cells into mice so that their immune systems create antibodies against foreign antigens.  Monoclonal antibodies target specific antigens on cancer cells and may enhance the patient's immune response. They can be administered alone or be linked (conjugated) to anticancer drugs, radioisotopes, or other biologic response modifiers. There are several therapeutic mechanisms for monoclonal antibodies:{{citation needed|date=November 2021}}
# Directly initiates [[apoptosis]] in the targeted cells
# [[Antibody-dependent cell-mediated cytotoxicity]] (ADCC) -- Recruits monocytes, macrophages, and natural killer cells to destroy the targeted cells
# [[Complement-dependent cytotoxicity]] (CDC)-- Initiates the [[complement system]] which activates the [[membrane attack complex]] causing cell lysis and death.
# Delivers chemotherapy or radiation in a targeted manner which allows higher concentrations to be administered
Monoclonal antibodies for treatment of B-cell malignancies<ref name="Bishop">Bishop, Michael R. [http://www.meds.com/immunotherapy/monoclonal_antibodies.html]{{Dead link|date=June 2024 |bot=InternetArchiveBot |fix-attempted=yes }}, "Monoclonal Antibodies", accessed 2/4/2011</ref>
* CD20.  Approximately 95% of B-cell lymphomas express CD20, but CD20 is not critical for B-cell survival.  Clonal B-cells spontaneously mutate the idiotypic region of their immunoglobulin. This high mutation rate makes them prone to the selection of B-cells lacking the CD20 antigen following treatment with CD20-targeting monoclonal antibodies.  As a result, CD20 may lose its effectiveness as a target after as little as one or two treatments with monoclonal antibodies such as rituximab.<ref name="Davis">{{cite journal |last1=Davis |first1=TA |last2=Czerwinski |first2=DK |last3=Levy |first3=R |title=Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression |journal=Clinical Cancer Research |volume=5 |issue=3 |pages=611–5 |year=1999 |pmid=10100713}}</ref>  A study in Japan found that approximately 26% of relapsed B-cell lymphoma patients lost CD20 expression during treatment with rituximab.  Lab tests involving 5-Aza showed that CD20 expression and rituximab sensitivity could be restored in some cases using epigenetic drug treatment.<ref name="Hiraga">{{cite journal |last1=Hiraga |first1=J. |last2=Tomita |first2=A. |last3=Sugimoto |first3=T. |last4=Shimada |first4=K. |last5=Ito |first5=M. |last6=Nakamura |first6=S. |last7=Kiyoi |first7=H. |last8=Kinoshita |first8=T. |last9=Naoe |first9=T. |title=Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance |journal=Blood |volume=113 |issue=20 |pages=4885–93 |year=2009 |pmid=19246561 |doi=10.1182/blood-2008-08-175208 |doi-access=free }}</ref>
** [[Rituximab]] (Rituxan.  The mechanism of action of Rituximab against DLBCL is not fully understood, but studies suggest that rituximab modulates cellular and molecular signal transduction pathways that regulate bcl-2-expression.  Interaction between bcl-2 expression and IL-10 growth factors may contribute to the resistance mechanisms of DLBCL to chemotherapy.<ref name="Park">{{cite journal  |vauthors=Park YH, Sohn SK, Kim JG, etal |title=Interaction between BCL2 and interleukin-10 gene polymorphisms alter outcomes of diffuse large B-cell lymphoma following rituximab plus CHOP chemotherapy |journal=Clin. Cancer Res. |volume=15 |issue=6 |pages=2107–15 |date=March 2009 |pmid=19276283 |doi=10.1158/1078-0432.CCR-08-1588 |url=http://clincancerres.aacrjournals.org/content/15/6/2107.full|doi-access=free }}</ref>
** [[Tositumomab]] (Bexxar).  Anti-CD20 conjugated with radionuclide iodine-131
** [[Ibritumomab tiuxetan]] (Zevalin).  Anti-CD20 conjugated with radioactive isotope (either yttrium-90 or indium-111)
* CD22.  Approximately 85% of DLBCLs express CD22.  It is expressed on pre-B and mature B cells, and expression is lost upon maturation to plasma cells.<ref name="Kahl">{{cite journal |last1=Kahl |first1=Brad |title=Chemotherapy Combinations With Monoclonal Antibodies in Non-Hodgkin's Lymphoma |journal=Seminars in Hematology |volume=45 |issue=2 |pages=90–4 |year=2008 |pmid=18381103 |pmc=2919066 |doi=10.1053/j.seminhematol.2008.02.003}}</ref>
** [[Epratuzumab]] (Lymphocide). After binding epratuzumab, CD22 is rapidly internalized. Cell death does not appear to be mediated by complement, but modest antibody-dependent cellular cytotoxicity and direct killing effects have been demonstrated.<ref name="Kahl"/>
* CD70.  In normal lymphoid tissues CD27 and its ligand CD70 have a restricted expression pattern, but a 1999 study found CD70 on 71% of large B-cell lymphomas.<ref name="Lens">{{cite journal |last1=Lens |first1=Susanne M. A. |last2=Drillenburg |first2=Paul |last3=Den Drijver |first3=Bianca F. A. |last4=Van Schijndel |first4=Gijs |last5=Pals |first5=Steven T. |last6=Van Lier |first6=Rene A. W. |last7=Van Oers |first7=Marinus H. J. |title=Aberrant expression and reverse signalling of CD70 on malignant B cells |journal=British Journal of Haematology |volume=106 |issue=2 |pages=491–503 |year=1999 |pmid=10460611 |doi=10.1046/j.1365-2141.1999.01573.x|doi-access=free }}</ref>
** [[Vorsetuzumab mafodotin]] (antibody conjugated to monomethyl auristatin F).  Monomethyl auristatin F is a mitotic inhibitor.  Preliminary data from a phase I clinical trial of vorsetuzumab mafodotin showed that of the 7 patients with non-Hodgkin lymphoma, one achieved complete remission, four were stable, one experienced progressive disease, and one was not evaluable.<ref name="SGN">{{cite press release |title=Seattle Genetics Reports Preliminary Data from Phase I Clinical Trial of SGN-75 |publisher=Seattle Genetics |date=October 11, 2010 |url=https://www.drugs.com/clinical_trials/seattle-genetics-reports-preliminary-data-phase-clinical-trial-sgn-75-10338.html |access-date=February 20, 2011}}</ref>
===[[Bcl-2 inhibitor]]s===
Apoptosis is one of the major mechanisms of cell death targeted by cancer therapies. Reduced susceptibility to apoptosis increases the resistance of cancer cells to radiation and cytotoxic agents. B-cell lymphoma-2 (Bcl-2) family members create a balance between pro and anti-apoptotic proteins. Pro-apoptotic proteins include Bax and Bak.  Anti-apoptotic proteins include Bcl-2, Bcl-X<sub>L</sub>, Bcl-w, Mcl-1. When anti-apoptotic family members are overexpressed, apoptotic cell death becomes less likely.<ref name="Kang">{{cite journal |last1=Kang |first1=M. H. |last2=Reynolds |first2=C. P. |title=Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy |journal=Clinical Cancer Research |volume=15 |issue=4 |pages=1126–32 |year=2009 |pmid=19228717 |doi=10.1158/1078-0432.CCR-08-0144 |pmc=3182268}}</ref>
* [[Oblimersen]] sodium (G3139, Genasense) targets BCL-2 mRNA
* [[ABT-737]] (oral form [[navitoclax]], ABT-263).  A small molecule that targets anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-X<sub>L</sub> and Bcl-w).  ABT-737 binds anti-apoptotic Bcl-2 proteins with an affinity two or three orders of magnitude more potent than previously reported compounds.  High basal levels of Mcl-1 expression are associated with resistance to ABT-737.  Combining ABT-737 with second agents that inactivate Mcl-1 may reduce this effect.<ref name="Kang"/>  ABT-737 has demonstrated single-agent efficacy against cell lines from lymphoid malignancies known to express high levels of Bcl-2, including DLBCL.  It has also been found to be synergistic with proteasome inhibitors.<ref name="Paoluzzi">{{cite journal  |vauthors=Paoluzzi L, Gonen M, Bhagat G, etal |title=The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies |journal=Blood |volume=112 |issue=7 |pages=2906–16 |date=October 2008 |pmid=18591385 |doi=10.1182/blood-2007-12-130781 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18591385|doi-access=free }}</ref>
* [[Fenretinide]].  A synthetic retinoid that induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs by triggering the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak.<ref name="Corazzari">{{cite journal |last1=Corazzari |first1=M |last2=Lovat |first2=P |last3=Oliverio |first3=S |last4=Disano |first4=F |last5=Donnorso |first5=R |last6=Redfern |first6=C |last7=Piacentini |first7=M |title=Fenretinide: A p53-independent way to kill cancer cells |journal=Biochemical and Biophysical Research Communications |volume=331 |issue=3 |pages=810–5 |year=2005 |pmid=15865936 |doi=10.1016/j.bbrc.2005.03.184}}</ref>
===mTOR (mammalian target of rapamycin) inhibitors===
[[mTOR inhibitor]]s :{{citation needed|date=November 2021}}
* [[Everolimus]]
* [[Temsirolimus]]
[[mTOR]] is a kinase enzyme inside the cell that regulates cell growth, proliferation, and survival.  mTOR inhibitors lead to cell cycle arrest in the G1 phase and also inhibits tumor angiogenesis by reducing synthesis of VEGF.{{citation needed|date=November 2021}}
A Phase II trial of Evorolimus on relapsed DLBCL patients showed a 30% Overall Response Rate (ORR).<ref name="Witzig">{{cite journal |last1=Witzig |first1=T E |last2=Reeder |first2=C B |last3=Laplant |first3=B R |last4=Gupta |first4=M |last5=Johnston |first5=P B |last6=Micallef |first6=I N |last7=Porrata |first7=L F |last8=Ansell |first8=S M |last9=Colgan |first9=J P |last10=Jacobsen |first10=E D |last11=Ghobrial |first11=I M |last12=Habermann |first12=T M |title=A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma |journal=Leukemia |volume=25 |issue=2 |pages=341–7 |year=2010 |pmid=21135857 |doi=10.1038/leu.2010.226|display-authors=8 |pmc=3049870 }}</ref>
===Syk (Spleen Tyrosine Kinase) inhibitors===
[[Syk inhibitor]]s include :
* [[Fostamatinib]]
* [[Tamatinib]]
Chronic signaling through the B-cell receptor appears to contribute to the survival of DLBCL.  These survival signals can be blocked by Syk inhibitors.  However, since the BCR signaling pathway is not as important to the GCB DLBCL as it is to the ABC subtype, Syk inhibitors may not be effective against GCB DLBCL<ref name="Flowers"/>
===[[Proteasome inhibitor]]s===
* [[Bortezomib]] (Velcade)
Proteasome inhibitors inhibit the NF-κB pathway.  Since this pathway is not a significant factor in GCB DLBCL, proteasome inhibitors have not been found to be effective against GCB DLBCL.  A clinical trial of bortezomib showed that bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated an ORR of 83% in ABC DLBCL and 13% in GCB DLBCL, suggesting that bortezomib enhances the activity of chemotherapy for ABC but not GCB DLBCL when combined with conventional chemotherapy.<ref name="Dunleavy">{{cite journal |last1=Dunleavy |first1=K. |last2=Pittaluga |first2=S. |last3=Czuczman |first3=M. S. |last4=Dave |first4=S. S. |last5=Wright |first5=G. |last6=Grant |first6=N. |last7=Shovlin |first7=M. |last8=Jaffe |first8=E. S. |last9=Janik |first9=J. E. |last10=Staudt |first10=L. M. |last11=Wilson |first11=W. H. |title=Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma |journal=Blood |volume=113 |issue=24 |pages=6069–76 |year=2009 |pmid=19380866 |pmc=2699229 |doi=10.1182/blood-2009-01-199679|display-authors=8 }}</ref>
==References==
{{Reflist|30em}}
{{Lymphoid malignancy}}
[[Category:Lymphoma]]