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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 Biology of NHL

Histologic diagnosis
of DLBCL

ABC DLBCL GCB DLBCL PMBL

Genes highly
expressed in
ABC DLBCL
Genes highly Fig 2. Application of gene expression
Diagnosis of expressed in profiling allows the distinction of histologically
molecular DLBCL GCB DLBCL undistinguishable molecular subtypes. Acti-
subtypes vated B-cell–like diffuse large B-cell lymphoma
Genes highly (ABC DLBCL), germinal center B-cell–like
expressed in (GCB) DLBCL, and primary mediastinal B-cell
GCB DLBCL/PMBL lymphoma (PMBL) can reproducibly be diag-
nosed by the use of DNA microarrays. These
subtypes use distinct molecular mechanisms
and oncogenic signaling pathways and re-
Genes highly
expressed in spond differently to conventional treatment.
PMBL

DLBCL Biopsies

1.0
0.8
Clinical
0.6 GCB DLBCL
implications ABC DLBCL
0.4
0.2
P < .001

0 1 2 3 4 5
Overall Survival (years)

frequently mutated by aberrant SHM in DLBCL.8 Some BCL6 muta-
tions occur in a negative autoregulatory site in the first noncoding
exon, thereby increasing BCL6 expression by relieving BCL6 of self-
repression.9 DLBCLs accumulate AID-dependent somatic mutations
in many other genes, including oncogenes such as MYC and PIM1.10
These mutations are generally within 1 to 2 kb of the start of transcrip-
tion and can alter protein function. However, the significance of these
mutations is currently unclear, as they have also been detected in
normal germinal center B cells.11
CSR also involves DNA breaks, and errors in its regulation can
lead to chromosomal switch translocations, which are frequently de-
tected in Burkitt’s lymphoma, multiple myeloma, and other lymphoid
malignancies.12,13 AID is the likely candidate to mediate these trans-
locations, as AID is required for spontaneous MYC/IgH translocations
in mice.14 Furthermore, the activated B-cell–like DLBCL subtype is
characterized by high AID expression and a high frequency of
switch translocations.15
B-cell lymphomas arise at different stages of differentiation, and
accordingly, pregerminal and postgerminal center lymphomas can be
distinguished (Fig 1). In the following sections of this review, the
biology of different lymphoma subtypes is discussed, with a special
emphasis on DLBCL.
DLBCL
DLBCL represents the most common type of malignant lymphoma
and accounts for approximately 30% to 40% of all cases in adults.16
DLBCL is heterogeneous with respect to morphology, biology, and
clinical presentation. Important insights into the molecular biology of
this entity have been achieved with the introduction of DNA microar-
rays, which provide a genome-wide profile of mRNA expression levels
in cancer samples. Gene expression profiling studies supported the
view that DLBCL is a heterogeneous diagnostic category, as three
molecular subtypes, termed GCB DLBCL, ABC DLBCL, and primary
mediastinal B-cell lymphoma (PMBL), could be detected, which are
indistinguishable using conventional diagnostic tools17-20 (Fig 2).

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 Nogai, Dörken, and Lenz
Table 1. Molecular DLBCL Subtypes Use Different Oncogenic Pathways
GCB ABC
Genomic Abnormality DLBCL (%) DLBCL (%) PMBL (%)
BCL2 translocation: t(14;18) 45 0 18
BCL2 amplification: 18q21 10 34 16
REL amplification: 2p13 28 5 19
CDKN2A homozygous deletion: 9p21 1 20 0 expression profile, but they are also addicted to different oncogenic
SPIB gain or amplification: 19q13 3 26 3 signaling pathways (Table 1). A frequent genetic abnormality detected
Trisomy 3 1 26 0 in roughly 45% of GCB DLBCLs is the t(14;18) translocation juxta-
Gain or amplification of 9p24 0 6 43
PRDM1 mutation/deletion (Blimp-1) 0 24 NA
BCL6 translocation 10 24 33
NOTE. Summarized from Rosenwald et al,18 Rosenwald et al,19 Pasqualucci
et al,23 Iqbal et al,24 Lenz et al,25 and Bea et al.26
Abbreviations: DLBCL, diffuse large B-cell lymphoma; GCB, germinal center
B-cell–like; ABC, activated B-cell–like; PMBL, primary mediastinal B-cell lym-
phoma; NA, not analyzed.
The gene expression profiles of these subtypes suggest that they
arise from B cells at different stages of differentiation. GCB DLBCLs
are derived from germinal center B cells, as they express many genes
specific for germinal center B lymphocytes. In contrast, the gene ex-
pression profile of ABC DLBCLs suggests that these lymphomas are
derived from B cells that are in the process of differentiating into
plasma cells.18 This hypothesis was based on the observation that ABC
DLBCLs express several genes characteristically expressed in plasma
cells. However, full plasma cell differentiation seems to be blocked.
Blimp-1, which is encoded by PRDM1, is a transcriptional repressor
that is required for plasmacytic differentiation.21 Inactivating muta-
tions and deletions of PRDM1 and subsequent loss of Blimp-1 expres-
sion have been detected in approximately one quarter of ABC
DLBCLs.22,23 Additionally, roughly 25% of ABC DLBCLs are charac-
terized by BCL6 translocations, and 26% of cases show gain or ampli-
fication of SPIB (Table 1). Both events repress Blimp-1 expression and
block differentiation.24,27 Thus the inactivation of PRDM1 by differ-
ent genetic aberrations provides direct evidence that a block in differ-
entiation is an important pathogenetic event in the molecular
pathogenesis of ABC DLBCL.
The third subtype of DLBCL, PMBL, often arises in young female
patients with a median age of only 30 to 35 years, with the mediasti-
num being the predominant site of lymphoma manifestation. PMBL,
which seems to originate from a rare B-cell subpopulation that resides
in the thymus, can be diagnosed by gene expression profiling, as it
shows a characteristic gene expression signature that clearly distin-
guishes it from GCB and ABC DLBCL.19,20 In contrast, PMBL cannot
be diagnosed reliably by clinical criteria and current diagnostic meth-
ods alone. Diagnosis of approximately 25% of cases assigned as PMBL
by conventional criteria was not confirmed by gene expression profil-
ing. These cases represented other DLBCL subtypes with mediastinal
involvement.19 Interestingly, gene expression profiling implicated a
molecular relationship between PMBL and nodular sclerosis
Hodgkin’s lymphoma (HL), as more than one third of genes that were
overexpressed in PMBL were also highly expressed in HL cell lines.19
Additionally, both PMBL and HL use certain oncogenic pathways,
such as the nuclear factor-␬B (NF-␬B) pathway,19,20 and harbor sim-
ilar genetic aberrations as amplification of chromosome 9p24.28,29
Thus these two lymphoma entities share several clinical, pathologic,
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and molecular features. These characteristics suggest that both PMBL
and HL might originate from a similar type of B-cell precursor.
Oncogenic Pathways Are Used Differentially in
Molecular DLBCL Subtypes
The DLBCL subtypes not only differ with respect to their gene
posing the BCL2 gene and the IgH locus and thereby deregulating the
antiapoptotic BCL2 protein. Interestingly, this abnormality is not
detectable in ABC DLBCL.18 Another characteristic feature of GCB
DLBCL is the deregulation of the phosphatase and tensin homolog
(PTEN) pathway by different genetic aberrations. GCB DLBCL exhib-
its PTEN deletions in 10% to 15% of cases, as well as amplifications of
miR-17-92 in roughly 15% of cases, which suppresses PTEN, implying
that deregulation of the PTEN–phosphatidylinositol 3-kinase (PI3k)
cascade plays an important role in the biology of this entity.25,30 An-
other frequent genetic alteration of GCB DLBCLs has recently been
described. Genomic DNA sequencing revealed somatic mutations of
the histone methyltransferase EZH2 in a single tyrosine in the EZH2
SET domain in roughly 20% of patient samples.31 The molecular
mechanisms by which mutated EZH2 might contribute to the patho-
genesis of GCB DLBCL are currently not known. However, strikingly,
these mutations were never detected in ABC DLCBL.31
In contrast, ABC DLBCLs are characterized by amplifications
affecting the BCL2 gene and loss of the CDKN2A (INK4A-ARF) tumor
suppressor locus.25 Another ABC DLBCL–specific abnormality in-
volves 19q. The gene SPIB seems to be important, as a translocation
between SPIB and the IgH locus was detected in an ABC DLBCL cell
line.15 SPIB belongs to the E26 transformation-specific family of tran-
scription factors and is required for normal germinal center reac-
tions.32 In ABC DLBCL, roughly one quarter of patients have a gain or
an amplification of 19q, with subsequent increase of SPIB mRNA
expression (Table 1). Furthermore, SPIB knockdown by short hairpin
RNAs (shRNAs), which mediate RNA interference, was toxic to ABC
DLBCL, but not to other lymphoma lines. These results implicate the
functional importance of SPIB in the biology of ABC DLBCL.25
A hallmark of ABC DLBCL biology is the constitutive activation
of the NF-␬B pathway, which promotes proliferation and differentia-
tion and suppresses apoptosis.33 NF-␬B signaling is mediated by a
group of structurally related proteins that are normally kept inactive in
the cytoplasm. Stimulation through various receptors activates the
NF-␬B factors, leading to their nuclear translocation and the trans-
activation of their target genes. A substantial number of genes
upregulated in ABC DLBCL are known NF-␬B target genes, in-
cluding BCL2, IL6, and IL10.33,34 Further evidence for the func-
tional importance of the NF-␬B signaling pathway in ABC DLBCL
was provided by experiments that showed that inhibition of NF-␬B
using small interfering molecules was toxic to ABC, but not to GCB
DLBCL cell lines, implying that ABC DLBCLs are addicted to
constitutive NF-␬B signaling.33,35
Insights that upstream pathways are crucial for constitutive
NF-␬B activity in ABC DLBCLs were obtained by an shRNA library
screen to identify novel oncogenes.36 shRNAs against CARD11,
MALT1, and BCL10 were toxic to ABC, but not to GCB DLBCL cell
lines. In lymphocytes, CARD11, MALT1, and BCL10 form a signaling
complex (CBM complex) after antigenic stimulation that leads to
JOURNAL OF CLINICAL ONCOLOGY
 Biology of NHL
NF-␬B activation.37 In contrast to lymphocytes in which the CBM
complex formation is transient, ABC DLBCLs have constitutively
activated CBM complexes. Interestingly, resequencing of CARD11
revealed activating missense mutations in CARD11 in approxi-
mately 10% of ABC DLBCL samples.38 Experimental introduction of
CARD11 mutants into lymphoma cell lines resulted in constitutive
NF-␬B activation, demonstrating that CARD11 functions as an onco-
gene in DLBCL.38 In ABC DLBCLs with wild-type CARD11, a
“chronic active” form of BCR signaling can be detected that activates
the CBM complex.39 The BCR is a multimeric complex that includes
the surface immunoglobulin molecule and noncovalently associated
two signaling subunits CD79A and CD79B. BCR stimulation activates
different kinases such as SRC family kinases, SYK, and BTK that
ultimately activate downstream pathways. The survival of ABC
DLBCL cell lines with wild-type CARD11 is dependent on BCR sig-
naling and the activity of downstream kinases. Roughly 20% of ABC
DLBCLs harbor mutations of CD79B and CD79A.39 The majority of
these aberrations alter a single tyrosine in the immunoreceptor
tyrosine-based activation motif of CD79B, which is phosphorylated
during BCR signaling. These mutant proteins increase cell surface
expression of the BCR and reduce the activation of LYN, which pro-
vides negative feedback to BCR signaling. These data strongly support
the view that chronic active BCR signaling plays an important role in
the molecular pathogenesis of ABC DLBCL.39
Two recent studies suggest an alternative mechanism of the con-
stitutively activated NF-␬B pathway detected in ABC DLBCL.40,41
Biallelic inactivation of the negative NF-␬B regulator A20 was detect-
able in approximately 30% of ABC DLBCL cases. Interestingly, A20
aberrations are also detectable in other lymphomas with constitutive
NF-␬B activity.41,42
PMBLs are characterized by amplifications of 9p24 (Table 1).25,28
In contrast, these abnormalities occur significantly less frequently in
ABC and GCB DLBCL.25 9p24 amplifications are associated with
upregulation of JAK2, a tyrosine kinase that regulates cytokine signal-
ing through STAT transcription factors. PD-L1 and PD-L2, which are
ligands for the PD receptor on T cells, are also upregulated in PMBL by
this amplification.19 Engagement of the PD receptor by its ligands
inhibits signaling through the T-cell receptor, suggesting that amplifi-
cation of these genes modulates the interaction between PMBL cells
and surrounding T cells.19 Constitutive activation of the NF-␬B sig-
naling pathway is another common feature of PMBL cells.19 The
molecular mechanisms that activate NF-␬B in PMBL are currently not
entirely understood. In approximately 30% of PMBL cases, the nega-
tive NF-␬B regulator A20 is inactivated.43
Survival Differences Between Molecular
DLBCL Subtypes
The clinical outcome of the DLBCL subtypes is significantly
different after standard treatment18,44 (Fig 2). Whereas the majority of
patients diagnosed with GCB DLBCL can be cured by a combined
approach of the anti-CD20 antibody rituximab and cyclophospha-
mide, doxorubicin, vincristine, and prednisone chemotherapy, more
than 50% of patients with ABC DLBCL will eventually succumb to
their disease.45 Gene expression profiling identified two gene signa-
tures, termed stromal-1 and stromal-2, that reflect the composition of
nonmalignant cells (ie, the tumor microenvironment), to be strongly
associated with patient outcome.45 The prognostically favorable
“stromal-1” signature reflects an extracellular matrix deposition and
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histiocytic infiltration. In contrast, the prognostically unfavorable
stromal-2 signature comprises many known endothelial cell genes.
DLBCL samples with high relative expression of the stromal-2 signa-
ture are associated with increased tumor blood vessel density. Thus the
stromal-2 signature may represent an angiogenic switch in which the
progression of a hyperplastic lesion to a fully malignant tumor is
accompanied by new blood vessel formation.46 It is tempting to spec-
ulate that the dependency of the tumor to the microenvironment
might be used therapeutically (eg, by inhibition of angiogenesis in
patients with high expression of the stromal-2 signature and increased
tumor blood vessel density).
In summary, DLBCL subtypes represent biologically distinct
molecular entities that are addicted to different oncogenic signaling
pathways. The distinction between ABC DLBCL, GCB DLBCL, and
PMBL is of major clinical importance, as they have significantly dif-
ferent survival rates after current standard rituximab and cyclophos-
phamide, doxorubicin, vincristine, and prednisone chemotherapy.
Outcome of patients with DLBCL seems to be influenced by the
combination of specific tumor characteristics and the composition of
the tumor microenvironment.
FOLLICULAR LYMPHOMA
Follicular lymphoma (FL) is the most frequent low-grade NHL and
accounts for approximately 20% of all malignant lymphomas.16 The
clinical course of FL can be highly variable, with overall survival rates
ranging from only a few to more than 20 years.
FL is derived from a germinal-center B cell and is characterized by
chromosomal translocations that dysregulate the expression of the
proto-oncogene BCL2, located on chromosome band 18q21 (Figs 1
and 3). In roughly 90% of FL cases, a t(14;18)(q32;q21) translocation
is detectable that juxtaposes the BCL2 gene and the IgH locus.6 Variant
translocations t(2;18) and t(18;22) to the Ig␬ and Ig␭ loci are consid-
ered as biologically equivalent but occur significantly less frequently. A
small fraction of FL cases do not harbor BCL2 translocations and do
not express BCL2 protein.47 The biology of these cases remains to be
elucidated. Interestingly, t(14;18)–positive cases differ with respect to
their gene expression profile from the t(14;18)–negative subgroup.
t(14;18)–negative cases display an enrichment of activated B-cell–like,
NF-␬B, proliferation and bystander cell gene expression signatures.48
The t(14;18) translocation, which is the initiating event in the
molecular pathogenesis of FL, is not sufficient to induce lymphoma
development, as BCL2-Ig transgenic mice only develop polyclonal
lymphoid hyperplasia.49 The BCL2 translocation occurs in the early
stages of B-cell development and is mediated by the RAG recombinase
proteins RAG1 and RAG2 that are responsible for V(D)J recombina-
tion. Intriguingly, a substantial number of healthy individuals harbor
the t(14;18) translocation in their normal blood B cells.50 These B cells
seem to have traversed the germinal center and display genotypic and
phenotypic features of FL.50
Thus far, additional pathogenic mechanisms that are required for
overt manifestation of FL remain poorly understood. In a recent
series, somatic mutations of the histone methyltransferase EZH2 were
detected in approximately 7% of FL samples.31 In another study,
somatic TNFRSF14 mutations have been identified in roughly 20% of
cases that were associated with adverse survival.51 However, the mo-
lecular mechanisms by which mutated EZH2 or TNFRSF14 might
© 2011 by American Society of Clinical Oncology 1807

Follicular
lymphoma
Influence of the tumor
microenvironment
Secondary events:
Immune-
p53 mutation
response-1
signature Chromosomal gains of 1q, 7, 8, 12q
Chromosomal deletions of 1, 6
Immune-
response-2
signature First hit:
FL biopsies
Translocation t(14;18)
Germinal-
center
B cell
contribute to the pathogenesis of FL are currently not known. By
classical cytogenetics, deletions in chromosome 1p and 6q as well as
gains in chromosome 7,12 and X could be demonstrated in 20% to
30% of FL samples.52,53 Several recent studies applied array-
comparative genomic hybridization to detect novel genetic aberra-
tions.54 However, thus far, no oncogene or tumor suppressor gene
affected by these genetic abnormalities could be identified. Inter-
estingly, other genes commonly involved in lymphomagenesis,
such as p53, are not deregulated in a substantial fraction of patients
with FL at diagnosis.55 In contrast, during histologic transforma-
tion into DLBCL, various genetic aberrations such as deletions or
mutations of CDKN2A are acquired.56 The role of p53 during trans-
formation remains controversial; in a recent series of patients with FL,
it was shown that p53 mutations are not associated with transforma-
tion to DLBCL.57
The importance of the tumor microenvironment in the clin-
ical course of FL has been demonstrated in a recent gene expression
profiling study of 191 FL patient samples (Fig 3).58 The length of
survival could be predicted at the time of diagnosis by measuring
two gene expression signatures consisting of genes known to be
expressed in normal immune cells. The immune-response 1 signa-
ture was associated with favorable outcome and reflects a mixture
of immune cells that is enriched for T cells. In contrast, the genes in
the immune-response 2 signature, which is associated with poor
overall survival, reflect an immune infiltrate that is enriched for
macrophages and/or dendritic cells.58 Several studies based either
on immunohistochemistry or reverse transcription polymerase
chain reaction confirmed the finding that the composition of the
microenvironment strongly influences prognosis of patients
with FL.59,60
In summary, despite the fact that our understanding of the inter-
action between follicular lymphoma and normal immune cells is still
rudimental, it seems conceivable that the composition and the nature
of the immune cells could have an impact on response to immune
modulatory therapies such as monoclonal antibodies.
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Nogai, Dörken, and Lenz
Fig 3. The t(14;18) is the initiating event
Malignant transformation in the molecular pathogenesis of follicular
lymphoma (FL). However, to induce lym-
phoma development, secondary genetic
DNA-damage response
alterations are required. An important feature
unknown target genes of FL biology is the interaction between lym-
unknown target genes phoma and normal immune cells. Measuring
the gene expression of the two microenviron-
mental signatures immune-response 1 and
Deregulation of BCL2 Apoptosis immune-response 2 can be used to predict
survival at diagnosis.
MANTLE CELL LYMPHOMA
Mantle cell lymphoma (MCL) accounts for 5% to 10% of all lym-
phoma cases in adults. It is derived in the vast majority of cases from a
naive pregerminal center B cell, as the Ig variable regions are unmu-
tated (Fig 1). Histologically, either a mantle zone, nodular, or dif-
fuse growth pattern can be observed.61 Cytologically, two main
variants can be distinguished, the classic subtype and the blastoid
variant (approximately 10% of cases).62 MCL displays an aggres-
sive clinical course, with a median survival of only 3 to 4 years.62
However, in a small fraction of patients, the disease has an indolent
behavior, and in these cases, a wait-and-watch strategy might be
justified. Recent work demonstrates that indolent MCL cases can
be identified either by gene expression profiling or by staining for
the transcription factor SOX11, as these MCL samples are charac-
terized by the absence of SOX11.63
Deregulation of cell cycle is the characteristic pathogenetic hall-
mark of MCL (Fig 4). Accordingly, the most important biologic prog-
nostic factor determined in several studies is the proliferation rate,
determined either by the number of mitoses or the Ki67 staining
index, with cases having a high proliferation index being associated
with adverse outcome.64 These results were confirmed by a large gene
expression profiling study that showed the prognostic impact of a gene
expression– based proliferation signature.65
Cell cycle deregulation is caused by different genetic abnor-
malities (Fig 4). MCLs are characterized by the chromosomal
translocation t(11;14) (q13;q32) that juxtaposes the CCND1 gene
to the IgH locus, leading to deregulation and overexpression of the
cell cycle regulator cyclin D1. Cyclin D1, which is normally not
expressed at high levels in normal B cells, plays an important role in
cellular proliferation by propelling cells from the G1 to S phase of
the cell cycle. Cyclin D1 forms heterodimers with the cyclin-
dependent kinases CDK4 and CDK6, thereby forming active ki-
nase complexes.66 These complexes phosphorylate and inactivate
JOURNAL OF CLINICAL ONCOLOGY
 Biology of NHL

Cell membrane

Mutation/
deletion

DNA damage ATM Mutation/

deletion Apoptosis
Fig 4. Mantle cell lymphoma (MCL)
p53 cases are characterized by deregulation of
DNA-damage response cell cycle control and DNA damage re-
Amplification Deletion
sponse. Genetic alterations detected in
ARF MDM2
MCL cases are depicted with a red star.
BMI1 Translocations affecting cyclin D1 as well
Cell cycle arrest
as amplifications of CDK4 facilitate G1 to
Deletion p21 S-phase transition via phosphorylation and
inactivation of retinoblastoma protein (RB).
Translocation t(11;14) INK4a Formation of the cyclin D1/CDK4/6 com-
plexes can alternatively be caused by inactiva-
Cyclin D1 tion of p16INK4a or amplification of BMI1.
Inactivation of both ataxia-telangiectasia mu-
Amplification tated (ATM) and p53 leads to dysregulation of
CDK4 CDK6 CDK2
CDK4
DNA damage response, resulting in a high
Cyclin D1 Cyclin E number of chromosomal aberrations and the
occurrence of tetraploid karyotypes.
CDK6
P

RB1 RB1

G1 Cell cycle G2

the tumor suppressor retinoblastoma protein (Rb) and thus sup-
press its protective effect on cell cycle progression (Fig 4). Equally
important, Cyclin D1/CDK4/6 complexes bind to p27kip1, an
inhibitor of cyclin E/CDK2 complexes. This sequestration of
p27kip1 allows the cyclin E/CDK2 complexes to promote S-phase
entry by phosphorylation of Rb.66
A small fraction of MCL samples seems to be cyclin D1
negative. Interestingly, these cases are histologically indistin-
guishable from cyclin D1–positive samples and additionally
have the same gene expression signature. These cases seem to
express either cyclin D2 or cyclin D3 to substitute for the lacking
cyclin D1 expression.67
Other genetic aberrations that deregulate cell cycle regulation are
homozygous deletions affecting p16INK4a and p14ARF on chromosome
9p21, which have been described in a substantial proportion of aggres-
sive MCL cases.68 p16INK4a inhibits the interaction between CDK4 and
⫺6 and cyclinD1 and thereby controls the phosphorylation and inac-
tivation of Rb.65 Some MCLs have amplification and/or overexpres-
sion of BMI1, which acts as a transcriptional repressor of the p16INK4A
locus.69 Additionally, CDK4 was found to be amplified and overex-
pressed in a fraction of highly aggressive MCLs (Fig 4).70 At last, the Rb
gene, has been found to be inactivated by deletions in MCL cases with
a high proliferation rate.71
Another pathogenetic feature of MCLs is the deregulation of
DNA damage response, as evidenced by the high number of chro-
mosomal aberrations and the occurrence of tetraploid karyotypes
in some aggressive MCL cases.72 In a large fraction of MCL sam-
ples, mutations and deletions of the ataxia-telangiectasia mutated
(ATM) gene, which plays an important role in the cellular response
to DNA damage, are detectable.73 Additionally, alterations in other
elements of the DNA response pathway have been detected in
MCL. p53 mutations occur in roughly 15% of MCL samples and
are associated with poor prognosis.74 p53 is upregulated in re-
sponse to cellular stress as DNA damage, resulting in cell cycle
arrest or apoptosis. Alternative mechanisms to inactivate p53 are
high levels of MDM2 expression in a small fraction of MCL cases or
loss of p14ARF, which stabilizes p53 by inhibition of MDM2-
mediated ubiquitination and degradation.70
Several recent studies identified additional genetic aberrations
that might play a role in the biology of MCL. A combined approach of
high-resolution gene expression and copy number profiling identified
CUL4A, ING1, and MCPH1 to be potentially involved in dysregula-
tion of proliferation and DNA damage response.75 Additionally, the
PI3k–mammalian target of rapamycin (mTOR) pathway seems to be
involved in the pathogenesis of MCL, as phosphorylation and activa-
tion of AKT is present in the majority of proliferative MCL cases.76

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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 Nogai, Dörken, and Lenz

for both FL and MCL, as both express BCL2 at high levels. Finally, the
PERSPECTIVES
PI3k-mTOR pathway might be attacked therapeutically in MCL.76 By
Significant progress in the understanding of the molecular patho- using novel compounds in malignant lymphomas in the context of
genesis of malignant lymphomas has been made in the last couple their biology, patient-specific treatments will become a clinical reality.
of years. Several novel compounds targeting oncogenic signaling
pathways are currently being tested in various trials in patients with
lymphoma. However, these approaches will only be successful if AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
these pathways are indeed used by the malignant cells. Techniques
such as gene expression profiling or cancer gene resequencing
The author(s) indicated no potential conflicts of interest.
should be applied to predict whether certain molecular subtypes
will respond favorably to the inhibitor treatment. Promising novel
targets in patients with DLBCL are BCL6,77 the NF-␬B pathway in AUTHOR CONTRIBUTIONS
ABC DLBCL or PMBL, components of the BCR signaling pathway
such as SYK or BTK in ABC DLBCL with wild-type CARD11, the Manuscript writing: All authors
PI3k-mTOR pathway, and BCL2. BCL2 might also be a suitable target Final approval of manuscript: All authors

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