Germinal center B-cell like diffuse large B-cell lymphoma

Last updated

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. [1] 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. [2] [ unreliable medical source? ]

Contents

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. [2] 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). [3] [ self-published source? ]

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. [2]

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 [1]

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. [4] 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. [5]

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. [4] 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 ]

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. [4]

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. [6] 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. [7]

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 ]

  1. Directly initiates apoptosis in the targeted cells
  2. Antibody-dependent cell-mediated cytotoxicity (ADCC) -- Recruits monocytes, macrophages, and natural killer cells to destroy the targeted cells
  3. Complement-dependent cytotoxicity (CDC)-- Initiates the complement system which activates the membrane attack complex causing cell lysis and death.
  4. Delivers chemotherapy or radiation in a targeted manner which allows higher concentrations to be administered

Monoclonal antibodies for treatment of B-cell malignancies [8]

Bcl-2 inhibitors

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-XL, Bcl-w, Mcl-1. When anti-apoptotic family members are overexpressed, apoptotic cell death becomes less likely. [15]

mTOR (mammalian target of rapamycin) inhibitors

mTOR inhibitors  :[ citation needed ]

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 ]

A Phase II trial of Evorolimus on relapsed DLBCL patients showed a 30% Overall Response Rate (ORR). [18]

Syk (Spleen Tyrosine Kinase) inhibitors

Syk inhibitors include :

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 [6]

Proteasome inhibitors

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. [19]

Related Research Articles

<span class="mw-page-title-main">Burkitt lymphoma</span> Medical condition

Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. The overall cure rate for Burkitt lymphoma in developed countries is about 90%, and it is worse in low-income countries. Burkitt lymphoma is uncommon in adults, in whom it has a worse prognosis.

<span class="mw-page-title-main">Bcl-2</span> Mammalian protein found in Homo sapiens

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">Rituximab</span> Pharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow injection into a vein. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

<span class="mw-page-title-main">Follicular lymphoma</span> Medical condition

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures in the tissues they invade. These structures are usually the dominant histological feature of this cancer.

<span class="mw-page-title-main">Primary effusion lymphoma</span> Medical condition

Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus. Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions, primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule which forms around breast implants. Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions.

<span class="mw-page-title-main">Diffuse large B-cell lymphoma</span> Type of blood cancer

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.

<span class="mw-page-title-main">Fas receptor</span> Mammalian protein found in Homo sapiens

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.

<span class="mw-page-title-main">Cancer immunology</span>

Cancer immunology is an interdisciplinary branch of biology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

<span class="mw-page-title-main">BCL6</span> Transcription factor for converting Naive T cells to TFH

Bcl-6 is a protein that in humans is encoded by the BCL6 gene. BCL6 is a master transcription factor for regulation of T follicular helper cells proliferation. BCL6 has three evolutionary conserved structural domains. The interaction of these domains with corepressors allows for germinal center development and leads to B cell proliferation.

<span class="mw-page-title-main">CD99</span> Protein-coding gene in humans

CD99 antigen, also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the CD99 gene in humans. The protein has a mass of 32 kD. Unusually for a gene present on the X chromosome, the CD99 gene does not undergo X inactivation, and it was the first such pseudoautosomal gene to be discovered in humans.

<span class="mw-page-title-main">Marginal zone B-cell lymphoma</span> Group of lymphomas

Marginal zone B-cell lymphomas, also known as marginal zone lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue, the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.

<span class="mw-page-title-main">Nodular lymphocyte predominant Hodgkin lymphoma</span> Medical condition

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a slow-growing CD20 positive form of Hodgkin lymphoma, a cancer of the immune systems B cells.

<span class="mw-page-title-main">ABT-737</span> Chemical compound

ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. First developed as a potential cancer chemotherapy, it was subsequently identified as a senolytic.

Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), also termed testicular diffuse large B-cell lymphoma and diffuse large B-cell lymphoma of the testes, is a variant of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large and diverse group of B-cell malignancies with the great majority (-85%) being typed as diffuse large B-cell lymphoma, not otherwise specified. PT-DLBCL is a variant of DLBCL, NOS that involves one or, in uncommon cases, both testicles. Other variants and subtypes of DLBCL may involve the testes by spreading to them from their primary sites of origin in other tissues. PT-DLBCL differs from these other DLBCL in that it begins in the testes and then may spread to other sites.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells become malignant, accumulate in the dermis and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

  1. 1 2 Lenz, G.; Wright, G. W.; Emre, N. C. T.; Kohlhammer, H.; Dave, S. S.; Davis, R. E.; Carty, S.; Lam, L. T.; et al. (2008). "Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways". Proceedings of the National Academy of Sciences. 105 (36): 13520–5. Bibcode:2008PNAS..10513520L. doi: 10.1073/pnas.0804295105 . PMC   2533222 . PMID   18765795.
  2. 1 2 3 Staudt, Louis M. Archived 2011-07-27 at the Wayback Machine , "Center for Cancer Research, Dr. Stoudt Description of Research", Updated 2/20/2009, accessed 1/28/2011
  3. ↑ Kimball, John W. , "Kimball's Biology Pages, BCL-2", accessed 1/29/2011
  4. 1 2 3 Shaffer, A. L.; Rosenwald, Andreas; Staudt, Louis M. (2002). "Decision making in the immune system: Lymphoid Malignancies: the dark side of B-cell differentiation". Nature Reviews Immunology. 2 (12): 920–32. doi:10.1038/nri953. PMID   12461565. S2CID   33328229.
  5. ↑ Klein, U.; Tu, Y; Stolovitzky, GA; Keller, JL; Haddad Jr, J; Miljkovic, V; Cattoretti, G; Califano, A; Dalla-Favera, R (2003). "Transcriptional analysis of the B cell germinal center reaction". Proceedings of the National Academy of Sciences. 100 (5): 2639–44. Bibcode:2003PNAS..100.2639K. doi: 10.1073/pnas.0437996100 . PMC   151393 . PMID   12604779.
  6. 1 2 Flowers, C. R.; Sinha, R.; Vose, J. M. (2010). "Improving Outcomes for Patients with Diffuse Large B-Cell Lymphoma". CA: A Cancer Journal for Clinicians. 60 (6): 393–408. doi: 10.3322/caac.20087 . PMID   21030533. S2CID   35745203.
  7. ↑ Maxwell, Steve A.; Li, Zenggang; Jaya, David; Ballard, Scott; Ferrell, Jay; Fu, Haian (2009). "14-3-3ζ Mediates Resistance of Diffuse Large B Cell Lymphoma to an Anthracycline-based Chemotherapeutic Regimen". Journal of Biological Chemistry. 284 (33): 22379–89. doi: 10.1074/jbc.M109.022418 . PMC   2755960 . PMID   19525224.
  8. ↑ Bishop, Michael R. , "Monoclonal Antibodies", accessed 2/4/2011
  9. ↑ Davis, TA; Czerwinski, DK; Levy, R (1999). "Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression". Clinical Cancer Research. 5 (3): 611–5. PMID   10100713.
  10. ↑ Hiraga, J.; Tomita, A.; Sugimoto, T.; Shimada, K.; Ito, M.; Nakamura, S.; Kiyoi, H.; Kinoshita, T.; Naoe, T. (2009). "Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance". Blood. 113 (20): 4885–93. doi: 10.1182/blood-2008-08-175208 . PMID   19246561.
  11. ↑ Park YH, Sohn SK, Kim JG, et al. (March 2009). "Interaction between BCL2 and interleukin-10 gene polymorphisms alter outcomes of diffuse large B-cell lymphoma following rituximab plus CHOP chemotherapy". Clin. Cancer Res. 15 (6): 2107–15. doi: 10.1158/1078-0432.CCR-08-1588 . PMID   19276283.
  12. 1 2 Kahl, Brad (2008). "Chemotherapy Combinations With Monoclonal Antibodies in Non-Hodgkin's Lymphoma". Seminars in Hematology. 45 (2): 90–4. doi:10.1053/j.seminhematol.2008.02.003. PMC   2919066 . PMID   18381103.
  13. ↑ Lens, Susanne M. A.; Drillenburg, Paul; Den Drijver, Bianca F. A.; Van Schijndel, Gijs; Pals, Steven T.; Van Lier, Rene A. W.; Van Oers, Marinus H. J. (1999). "Aberrant expression and reverse signalling of CD70 on malignant B cells". British Journal of Haematology. 106 (2): 491–503. doi: 10.1046/j.1365-2141.1999.01573.x . PMID   10460611.
  14. ↑ "Seattle Genetics Reports Preliminary Data from Phase I Clinical Trial of SGN-75" (Press release). Seattle Genetics. October 11, 2010. Retrieved February 20, 2011.
  15. 1 2 Kang, M. H.; Reynolds, C. P. (2009). "Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy". Clinical Cancer Research. 15 (4): 1126–32. doi:10.1158/1078-0432.CCR-08-0144. PMC   3182268 . PMID   19228717.
  16. ↑ Paoluzzi L, Gonen M, Bhagat G, et al. (October 2008). "The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies". Blood. 112 (7): 2906–16. doi: 10.1182/blood-2007-12-130781 . PMID   18591385.
  17. ↑ Corazzari, M; Lovat, P; Oliverio, S; Disano, F; Donnorso, R; Redfern, C; Piacentini, M (2005). "Fenretinide: A p53-independent way to kill cancer cells". Biochemical and Biophysical Research Communications. 331 (3): 810–5. doi:10.1016/j.bbrc.2005.03.184. PMID   15865936.
  18. ↑ Witzig, T E; Reeder, C B; Laplant, B R; Gupta, M; Johnston, P B; Micallef, I N; Porrata, L F; Ansell, S M; et al. (2010). "A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma". Leukemia. 25 (2): 341–7. doi:10.1038/leu.2010.226. PMC   3049870 . PMID   21135857.
  19. ↑ Dunleavy, K.; Pittaluga, S.; Czuczman, M. S.; Dave, S. S.; Wright, G.; Grant, N.; Shovlin, M.; Jaffe, E. S.; et al. (2009). "Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma". Blood. 113 (24): 6069–76. doi:10.1182/blood-2009-01-199679. PMC   2699229 . PMID   19380866.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.