VOLUME 29 䡠 NUMBER
JOURNAL OF CLINICAL ONCOLOGY
From Charité–Universitätsmedizin
Berlin, Berlin, Germany.
Submitted October 18, 2010; accepted
January 4, 2011; published online
ahead of print at www.jco.org on April
11, 2011.
Supported by research grants to G.L.
from the German Research Foundation,
the Deutsche Krebshilfe, and the Else
Kröner-Fresenius-Stiftung.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Georg Lenz, MD,
Department of Hematology, Oncology
and Tumor Immunology, Charité–
Universitätsmedizin Berlin, Augusten-
burger Platz 1, Am Forum 4, Berlin
13353, Germany; e-mail: georg.lenz@
charite.de.
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2914-1803/$20.00
DOI: 10.1200/JCO.2010.33.3252
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14 䡠 MAY 10 2011
R E V I E W A R T I C L E
Pathogenesis of Non-Hodgkin’s Lymphoma
Hendrik Nogai, Bernd Dörken, and Georg Lenz
A B S T R A C T
The understanding of the molecular pathogenesis of non-Hodgkin’s lymphomas (NHL) has
significantly improved in recent years. Advances in molecular biology and genetics lead to the
identification and characterization of several oncogenic pathways involved in lymphomagenesis.
This knowledge will ultimately lead to improved diagnostic and therapeutic strategies for patients
with NHL. This review summarizes current concepts of the molecular pathogenesis of the most
common NHL subtypes, with a special emphasis on diffuse large B-cell lymphoma, the most
common lymphoma subtype.
J Clin Oncol 29:1803-1811. © 2011 by American Society of Clinical Oncology
lymphoma development. Accordingly, secondary
INTRODUCTION
genetic alterations are required for the full malignant
Non-Hodgkin’s lymphomas (NHLs) represent a transformation. In this review, we summarize the
heterogeneous group of malignancies that arise current knowledge on the biology of the most com-
from the lymphoid system. Recent advances in mo- mon NHL subtypes.
lecular genetics have significantly deepened our un-
derstanding of the biology of these diseases. The
B-CELL DEVELOPMENT AND LYMPHOMAGENESIS
introduction of gene expression profiling especially
has led to the discovery of novel oncogenic pathways
B-cell lymphomas arise during different steps of
involved in the process of malignant transforma-
B-lymphocyte development and represent their ma-
tion. Equally important, these analyses have identi-
lignant counterpart (Fig 1). B-cell development en-
fied novel molecular lymphoma subtypes that are
compasses different stages and is initiated in the
histologically indistinguishable. In diffuse large
primary lymphoid organs with subsequent differen-
B-cell lymphoma (DLBCL), the distinction of the
tiation in secondary lymphoid tissues such as lymph
germinal center B-cell–like (GCB) DLBCL and acti- nodes, spleen, or tonsils. During these stages of de-
vated B-cell–like (ABC) DLBCL subtypes is begin- velopment, several DNA modifications occur that
ning to translate into the clinic, as these diagnostic are essential for a normal immune response. How-
categories have significantly different survival rates ever, these modifications might predispose to ge-
after standard treatment. Similarly, the molecular netic abnormalities leading to lymphoma evolution.
distinction using gene expression profiling of The development of B cells in the bone marrow
DLBCL and Burkitt’s lymphoma (BL) is of major is initiated by random recombination of genes that
clinical importance, as BL requires more intensive encode the variable regions of the heavy and light
treatment strategies. These examples evidence that antibody chains to form the B-cell receptor (BCR).
the routine application of gene expression profiling This process is referred as V(D)J recombination and
will eventually lead to the establishment of a molec- involves double-stranded DNA breaks by recombi-
ular classification of malignant lymphoma. nation activating gene 1 (RAG1) and recombination
Similar to other types of cancer, NHLs arise by activating gene 2 (RAG2), which are resolved by
a multistep accumulation of genetic aberrations that nonhomologous end-joining repair processes.1
induce a selective growth advantage of the malig- The immunoglobulin heavy chain genes (IgH) are
nant clone. Recurrent translocations, which occur assembled from various V (variable), D (diversity)
during different steps of B-cell differentiation, are and J (joining) elements, whereas the light chain is
often an initial step in the malignant transformation recombined from V and J elements.2 During this
(Fig 1). These translocations lead to deregulated ex- process, only cells that have acquired heavy and
pression of oncogenes that often control cell prolif- light chain variable region genes that can be trans-
eration, survival, and differentiation. Interestingly, lated into protein will survive, whereas all other
these translocations alone are often insufficient for cells will undergo apoptosis.2 Once the BCR is
© 2011 by American Society of Clinical Oncology 1803
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 Nogai, Dörken, and Lenz

Follicular GCB Burkitt

lymphoma DLBCL lymphoma

Centro-
blast
Centro-
cyte
Germinal-center reaction
SMH and
CSR

AID

Aberrant SMH
and switch
translocations

Blimp1
Mantle
le cell ABC Multiple
lymphoma
homa DLBCL myeloma
XBP1

V(D)J BCL6
recombination

RAG1 RAG2
Pro Pre Naive Plasma- Plasma
B cell B cell B cell blast cell
Antigen
contact
t(14;18) Ig secretion
t(11;14)

Fig 1. Lymphomas arise at different stages of B-cell differentiation. Specific recombination events are prone to the development of chromosomal aberrations.
Recombination activating gene 1 (RAG1)-dependent and RAG2-dependent V(D)J recombination takes place in the bone marrow. The potentially resulting t(14;18) and
t(11;14) represent critical first steps in lymphomagenesis of different lymphoma subtypes. After antigen contact, the stimulated B cells migrate to the lymph node and
form the germinal center after upregulation of BCL6. The events during the germinal center reaction include activation-induced cytidine deaminase (AID) –mediated
somatic hypermutation and class-switch recombination, which are critical events for lymphoma evolution. The germinal center reaction is terminated by the
differentiation of B cells into plasma cells. XBP1 and Blimp-1 are key regulators for plasmacytic differentiation. GCB DLBCL, germinal center B-cell–like diffuse large
B-cell lymphoma; SMH, somatic hypermutation; CSR, class-switch recombination; ABC DLBCL, activated B-cell–like diffuse large B-cell lymphoma; Ig, immunoglobulin.

expressed, the lymphocytes leave the bone marrow and become
mature, naive B cells.
On antigen-induced B-cell activation, the germinal center reac-
tion in secondary lymphoid tissues is initiated. During the germinal
center reaction at least two distinct DNA modifications—somatic
hypermutation (SHM) and class switch recombination (CSR)—
occur (Fig 1). Both reactions are mediated by the B-cell specific en-
zyme activation-induced cytidine deaminase (AID).3 SHM modifies
the Ig variable region by introducing mutations, small deletions, or
insertions to produce antibodies with increased affinity for the immu-
nizing antigen.4 In contrast, CSR is a process by which the heavy chain
class changes from IgM to IgG, IgA, or IgE. CSR occurs by DNA
recombination within highly repetitive switch regions located 5⬘ of
each constant region.5 After the germinal center reaction, B cells de-
velop into memory B cells or plasma cells.
The tightly controlled steps in B-cell development, however,
can go awry, and lymphomas may arise. V(D)J recombination,
SHM, and CSR especially represent critical processes that might
predispose to these malignancies. Examples of translocations oc-
curring during V(D)J recombination are t(14;18) and t(11;14).
The t(14;18), which is detected in virtually all cases of follicular
lymphoma and a fraction of diffuse large B-cell lymphoma
(DLBCL) cases, involves the BCL2 gene and the IgH locus, leading
to dysregulation of BCL2.6 The t(14;18) is mediated by the RAG
recombinase proteins, which cleave at J segments in the IgH locus
and at an unusual non–B-form DNA structure in BCL2.7 Similar to
t(14;18), t(11;14) juxtaposes the CCND1 gene to the IgH locus,
leading to overexpression of cyclin D1.
SHM has also been suggested to play an important role in lym-
phomagenesis. AID can mutate genes in addition to Ig genes. BCL6 is

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