VOLUME 29 䡠 NUMBER 14 䡠 MAY 10 2011

JOURNAL OF CLINICAL ONCOLOGY 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
From Charité–Universitätsmedizin
Berlin, Berlin, Germany. A B S T R A C T

Submitted October 18, 2010; accepted The understanding of the molecular pathogenesis of non-Hodgkin’s lymphomas (NHL) has
January 4, 2011; published online
ahead of print at www.jco.org on April
significantly improved in recent years. Advances in molecular biology and genetics lead to the
11, 2011. identification and characterization of several oncogenic pathways involved in lymphomagenesis.
This knowledge will ultimately lead to improved diagnostic and therapeutic strategies for patients
Supported by research grants to G.L.
from the German Research Foundation,
with NHL. This review summarizes current concepts of the molecular pathogenesis of the most
the Deutsche Krebshilfe, and the Else common NHL subtypes, with a special emphasis on diffuse large B-cell lymphoma, the most
Kröner-Fresenius-Stiftung. common lymphoma subtype.
Authors’ disclosures of potential con-
flicts of interest and author contribu- J Clin Oncol 29:1803-1811. © 2011 by American Society of Clinical Oncology
tions are found at the end of this
article.
lymphoma development. Accordingly, secondary
Corresponding author: Georg Lenz, MD, INTRODUCTION
Department of Hematology, Oncology
genetic alterations are required for the full malignant
and Tumor Immunology, Charité– Non-Hodgkin’s lymphomas (NHLs) represent a transformation. In this review, we summarize the
Universitätsmedizin Berlin, Augusten- heterogeneous group of malignancies that arise current knowledge on the biology of the most com-
burger Platz 1, Am Forum 4, Berlin
from the lymphoid system. Recent advances in mo- mon NHL subtypes.
13353, Germany; e-mail: georg.lenz@
charite.de. lecular genetics have significantly deepened our un-
© 2011 by American Society of Clinical derstanding of the biology of these diseases. The
B-CELL DEVELOPMENT AND LYMPHOMAGENESIS
Oncology introduction of gene expression profiling especially
0732-183X/11/2914-1803/$20.00 has led to the discovery of novel oncogenic pathways
B-cell lymphomas arise during different steps of
DOI: 10.1200/JCO.2010.33.3252 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

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

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

1804 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 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- distinguished (Fig 1). In the following sections of this review, the
tions occur in a negative autoregulatory site in the first noncoding biology of different lymphoma subtypes is discussed, with a special
exon, thereby increasing BCL6 expression by relieving BCL6 of self- emphasis on DLBCL.
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- DLBCL
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 DLBCL represents the most common type of malignant lymphoma
CSR also involves DNA breaks, and errors in its regulation can and accounts for approximately 30% to 40% of all cases in adults.16
lead to chromosomal switch translocations, which are frequently de- DLBCL is heterogeneous with respect to morphology, biology, and
tected in Burkitt’s lymphoma, multiple myeloma, and other lymphoid clinical presentation. Important insights into the molecular biology of
malignancies.12,13 AID is the likely candidate to mediate these trans- this entity have been achieved with the introduction of DNA microar-
locations, as AID is required for spontaneous MYC/IgH translocations rays, which provide a genome-wide profile of mRNA expression levels
in mice.14 Furthermore, the activated B-cell–like DLBCL subtype is in cancer samples. Gene expression profiling studies supported the
characterized by high AID expression and a high frequency of view that DLBCL is a heterogeneous diagnostic category, as three
switch translocations.15 molecular subtypes, termed GCB DLBCL, ABC DLBCL, and primary
B-cell lymphomas arise at different stages of differentiation, and mediastinal B-cell lymphoma (PMBL), could be detected, which are
accordingly, pregerminal and postgerminal center lymphomas can be indistinguishable using conventional diagnostic tools17-20 (Fig 2).

www.jco.org © 2011 by American Society of Clinical Oncology 1805

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

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

and molecular features. These characteristics suggest that both PMBL

Table 1. Molecular DLBCL Subtypes Use Different Oncogenic Pathways
and HL might originate from a similar type of B-cell precursor.
GCB ABC
Genomic Abnormality DLBCL (%) DLBCL (%) PMBL (%)
Oncogenic Pathways Are Used Differentially in
BCL2 translocation: t(14;18) 45 0 18
Molecular DLBCL Subtypes
BCL2 amplification: 18q21 10 34 16
REL amplification: 2p13 28 5 19
The DLBCL subtypes not only differ with respect to their gene
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 posing the BCL2 gene and the IgH locus and thereby deregulating the
PRDM1 mutation/deletion (Blimp-1) 0 24 NA antiapoptotic BCL2 protein. Interestingly, this abnormality is not
BCL6 translocation 10 24 33
detectable in ABC DLBCL.18 Another characteristic feature of GCB
NOTE. Summarized from Rosenwald et al,18 Rosenwald et al,19 Pasqualucci DLBCL is the deregulation of the phosphatase and tensin homolog
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 (PTEN) pathway by different genetic aberrations. GCB DLBCL exhib-
B-cell–like; ABC, activated B-cell–like; PMBL, primary mediastinal B-cell lym- its PTEN deletions in 10% to 15% of cases, as well as amplifications of
phoma; NA, not analyzed.
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
The gene expression profiles of these subtypes suggest that they described. Genomic DNA sequencing revealed somatic mutations of
arise from B cells at different stages of differentiation. GCB DLBCLs the histone methyltransferase EZH2 in a single tyrosine in the EZH2
are derived from germinal center B cells, as they express many genes SET domain in roughly 20% of patient samples.31 The molecular
specific for germinal center B lymphocytes. In contrast, the gene ex- mechanisms by which mutated EZH2 might contribute to the patho-
pression profile of ABC DLBCLs suggests that these lymphomas are genesis of GCB DLBCL are currently not known. However, strikingly,
derived from B cells that are in the process of differentiating into these mutations were never detected in ABC DLCBL.31
plasma cells.18 This hypothesis was based on the observation that ABC In contrast, ABC DLBCLs are characterized by amplifications
DLBCLs express several genes characteristically expressed in plasma affecting the BCL2 gene and loss of the CDKN2A (INK4A-ARF) tumor
cells. However, full plasma cell differentiation seems to be blocked. suppressor locus.25 Another ABC DLBCL–specific abnormality in-
Blimp-1, which is encoded by PRDM1, is a transcriptional repressor volves 19q. The gene SPIB seems to be important, as a translocation
that is required for plasmacytic differentiation.21 Inactivating muta- between SPIB and the IgH locus was detected in an ABC DLBCL cell
tions and deletions of PRDM1 and subsequent loss of Blimp-1 expres- line.15 SPIB belongs to the E26 transformation-specific family of tran-
sion have been detected in approximately one quarter of ABC scription factors and is required for normal germinal center reac-
DLBCLs.22,23 Additionally, roughly 25% of ABC DLBCLs are charac- tions.32 In ABC DLBCL, roughly one quarter of patients have a gain or
terized by BCL6 translocations, and 26% of cases show gain or ampli- an amplification of 19q, with subsequent increase of SPIB mRNA
fication of SPIB (Table 1). Both events repress Blimp-1 expression and expression (Table 1). Furthermore, SPIB knockdown by short hairpin
block differentiation.24,27 Thus the inactivation of PRDM1 by differ- RNAs (shRNAs), which mediate RNA interference, was toxic to ABC
ent genetic aberrations provides direct evidence that a block in differ- DLBCL, but not to other lymphoma lines. These results implicate the
entiation is an important pathogenetic event in the molecular functional importance of SPIB in the biology of ABC DLBCL.25
pathogenesis of ABC DLBCL. A hallmark of ABC DLBCL biology is the constitutive activation
The third subtype of DLBCL, PMBL, often arises in young female of the NF-␬B pathway, which promotes proliferation and differentia-
patients with a median age of only 30 to 35 years, with the mediasti- tion and suppresses apoptosis.33 NF-␬B signaling is mediated by a
num being the predominant site of lymphoma manifestation. PMBL, group of structurally related proteins that are normally kept inactive in
which seems to originate from a rare B-cell subpopulation that resides the cytoplasm. Stimulation through various receptors activates the
in the thymus, can be diagnosed by gene expression profiling, as it NF-␬B factors, leading to their nuclear translocation and the trans-
shows a characteristic gene expression signature that clearly distin- activation of their target genes. A substantial number of genes
guishes it from GCB and ABC DLBCL.19,20 In contrast, PMBL cannot upregulated in ABC DLBCL are known NF-␬B target genes, in-
be diagnosed reliably by clinical criteria and current diagnostic meth- cluding BCL2, IL6, and IL10.33,34 Further evidence for the func-
ods alone. Diagnosis of approximately 25% of cases assigned as PMBL tional importance of the NF-␬B signaling pathway in ABC DLBCL
by conventional criteria was not confirmed by gene expression profil- was provided by experiments that showed that inhibition of NF-␬B
ing. These cases represented other DLBCL subtypes with mediastinal using small interfering molecules was toxic to ABC, but not to GCB
involvement.19 Interestingly, gene expression profiling implicated a DLBCL cell lines, implying that ABC DLBCLs are addicted to
molecular relationship between PMBL and nodular sclerosis constitutive NF-␬B signaling.33,35
Hodgkin’s lymphoma (HL), as more than one third of genes that were Insights that upstream pathways are crucial for constitutive
overexpressed in PMBL were also highly expressed in HL cell lines.19 NF-␬B activity in ABC DLBCLs were obtained by an shRNA library
Additionally, both PMBL and HL use certain oncogenic pathways, screen to identify novel oncogenes.36 shRNAs against CARD11,
such as the nuclear factor-␬B (NF-␬B) pathway,19,20 and harbor sim- MALT1, and BCL10 were toxic to ABC, but not to GCB DLBCL cell
ilar genetic aberrations as amplification of chromosome 9p24.28,29 lines. In lymphocytes, CARD11, MALT1, and BCL10 form a signaling
Thus these two lymphoma entities share several clinical, pathologic, complex (CBM complex) after antigenic stimulation that leads to

1806 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 Biology of NHL

NF-␬B activation.37 In contrast to lymphocytes in which the CBM histiocytic infiltration. In contrast, the prognostically unfavorable
complex formation is transient, ABC DLBCLs have constitutively stromal-2 signature comprises many known endothelial cell genes.
activated CBM complexes. Interestingly, resequencing of CARD11 DLBCL samples with high relative expression of the stromal-2 signa-
revealed activating missense mutations in CARD11 in approxi- ture are associated with increased tumor blood vessel density. Thus the
mately 10% of ABC DLBCL samples.38 Experimental introduction of stromal-2 signature may represent an angiogenic switch in which the
CARD11 mutants into lymphoma cell lines resulted in constitutive progression of a hyperplastic lesion to a fully malignant tumor is
NF-␬B activation, demonstrating that CARD11 functions as an onco- accompanied by new blood vessel formation.46 It is tempting to spec-
gene in DLBCL.38 In ABC DLBCLs with wild-type CARD11, a ulate that the dependency of the tumor to the microenvironment
“chronic active” form of BCR signaling can be detected that activates might be used therapeutically (eg, by inhibition of angiogenesis in
the CBM complex.39 The BCR is a multimeric complex that includes patients with high expression of the stromal-2 signature and increased
the surface immunoglobulin molecule and noncovalently associated tumor blood vessel density).
two signaling subunits CD79A and CD79B. BCR stimulation activates In summary, DLBCL subtypes represent biologically distinct
different kinases such as SRC family kinases, SYK, and BTK that molecular entities that are addicted to different oncogenic signaling
ultimately activate downstream pathways. The survival of ABC pathways. The distinction between ABC DLBCL, GCB DLBCL, and
DLBCL cell lines with wild-type CARD11 is dependent on BCR sig- PMBL is of major clinical importance, as they have significantly dif-
naling and the activity of downstream kinases. Roughly 20% of ABC ferent survival rates after current standard rituximab and cyclophos-
DLBCLs harbor mutations of CD79B and CD79A.39 The majority of phamide, doxorubicin, vincristine, and prednisone chemotherapy.
these aberrations alter a single tyrosine in the immunoreceptor Outcome of patients with DLBCL seems to be influenced by the
tyrosine-based activation motif of CD79B, which is phosphorylated combination of specific tumor characteristics and the composition of
during BCR signaling. These mutant proteins increase cell surface the tumor microenvironment.
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 FOLLICULAR LYMPHOMA
the molecular pathogenesis of ABC DLBCL.39
Two recent studies suggest an alternative mechanism of the con- Follicular lymphoma (FL) is the most frequent low-grade NHL and
stitutively activated NF-␬B pathway detected in ABC DLBCL.40,41 accounts for approximately 20% of all malignant lymphomas.16 The
Biallelic inactivation of the negative NF-␬B regulator A20 was detect- clinical course of FL can be highly variable, with overall survival rates
able in approximately 30% of ABC DLBCL cases. Interestingly, A20 ranging from only a few to more than 20 years.
aberrations are also detectable in other lymphomas with constitutive FL is derived from a germinal-center B cell and is characterized by
NF-␬B activity.41,42 chromosomal translocations that dysregulate the expression of the
PMBLs are characterized by amplifications of 9p24 (Table 1).25,28 proto-oncogene BCL2, located on chromosome band 18q21 (Figs 1
In contrast, these abnormalities occur significantly less frequently in and 3). In roughly 90% of FL cases, a t(14;18)(q32;q21) translocation
ABC and GCB DLBCL.25 9p24 amplifications are associated with is detectable that juxtaposes the BCL2 gene and the IgH locus.6 Variant
upregulation of JAK2, a tyrosine kinase that regulates cytokine signal- translocations t(2;18) and t(18;22) to the Ig␬ and Ig␭ loci are consid-
ing through STAT transcription factors. PD-L1 and PD-L2, which are ered as biologically equivalent but occur significantly less frequently. A
ligands for the PD receptor on T cells, are also upregulated in PMBL by small fraction of FL cases do not harbor BCL2 translocations and do
this amplification.19 Engagement of the PD receptor by its ligands not express BCL2 protein.47 The biology of these cases remains to be
inhibits signaling through the T-cell receptor, suggesting that amplifi- elucidated. Interestingly, t(14;18)–positive cases differ with respect to
cation of these genes modulates the interaction between PMBL cells their gene expression profile from the t(14;18)–negative subgroup.
and surrounding T cells.19 Constitutive activation of the NF-␬B sig- t(14;18)–negative cases display an enrichment of activated B-cell–like,
naling pathway is another common feature of PMBL cells.19 The NF-␬B, proliferation and bystander cell gene expression signatures.48
molecular mechanisms that activate NF-␬B in PMBL are currently not The t(14;18) translocation, which is the initiating event in the
entirely understood. In approximately 30% of PMBL cases, the nega- molecular pathogenesis of FL, is not sufficient to induce lymphoma
tive NF-␬B regulator A20 is inactivated.43 development, as BCL2-Ig transgenic mice only develop polyclonal
lymphoid hyperplasia.49 The BCL2 translocation occurs in the early
Survival Differences Between Molecular stages of B-cell development and is mediated by the RAG recombinase
DLBCL Subtypes proteins RAG1 and RAG2 that are responsible for V(D)J recombina-
The clinical outcome of the DLBCL subtypes is significantly tion. Intriguingly, a substantial number of healthy individuals harbor
different after standard treatment18,44 (Fig 2). Whereas the majority of the t(14;18) translocation in their normal blood B cells.50 These B cells
patients diagnosed with GCB DLBCL can be cured by a combined seem to have traversed the germinal center and display genotypic and
approach of the anti-CD20 antibody rituximab and cyclophospha- phenotypic features of FL.50
mide, doxorubicin, vincristine, and prednisone chemotherapy, more Thus far, additional pathogenic mechanisms that are required for
than 50% of patients with ABC DLBCL will eventually succumb to overt manifestation of FL remain poorly understood. In a recent
their disease.45 Gene expression profiling identified two gene signa- series, somatic mutations of the histone methyltransferase EZH2 were
tures, termed stromal-1 and stromal-2, that reflect the composition of detected in approximately 7% of FL samples.31 In another study,
nonmalignant cells (ie, the tumor microenvironment), to be strongly somatic TNFRSF14 mutations have been identified in roughly 20% of
associated with patient outcome.45 The prognostically favorable cases that were associated with adverse survival.51 However, the mo-
“stromal-1” signature reflects an extracellular matrix deposition and lecular mechanisms by which mutated EZH2 or TNFRSF14 might

www.jco.org © 2011 by American Society of Clinical Oncology 1807

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

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

Follicular
lymphoma

Fig 3. The t(14;18) is the initiating event

Influence of the tumor Malignant transformation in the molecular pathogenesis of follicular
microenvironment
Secondary events: lymphoma (FL). However, to induce lym-
Immune-
phoma development, secondary genetic
p53 mutation DNA-damage response
response-1 alterations are required. An important feature
signature Chromosomal gains of 1q, 7, 8, 12q unknown target genes of FL biology is the interaction between lym-
Chromosomal deletions of 1, 6 unknown target genes phoma and normal immune cells. Measuring
Immune-
response-2 the gene expression of the two microenviron-
signature First hit: mental signatures immune-response 1 and
FL biopsies
Translocation t(14;18) Deregulation of BCL2 Apoptosis immune-response 2 can be used to predict
survival at diagnosis.

Germinal-
center
B cell

contribute to the pathogenesis of FL are currently not known. By

MANTLE CELL LYMPHOMA
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- Mantle cell lymphoma (MCL) accounts for 5% to 10% of all lym-
comparative genomic hybridization to detect novel genetic aberra- phoma cases in adults. It is derived in the vast majority of cases from a
tions.54 However, thus far, no oncogene or tumor suppressor gene naive pregerminal center B cell, as the Ig variable regions are unmu-
affected by these genetic abnormalities could be identified. Inter- tated (Fig 1). Histologically, either a mantle zone, nodular, or dif-
estingly, other genes commonly involved in lymphomagenesis, fuse growth pattern can be observed.61 Cytologically, two main
such as p53, are not deregulated in a substantial fraction of patients variants can be distinguished, the classic subtype and the blastoid
with FL at diagnosis.55 In contrast, during histologic transforma- variant (approximately 10% of cases).62 MCL displays an aggres-
tion into DLBCL, various genetic aberrations such as deletions or sive clinical course, with a median survival of only 3 to 4 years.62
mutations of CDKN2A are acquired.56 The role of p53 during trans- However, in a small fraction of patients, the disease has an indolent
formation remains controversial; in a recent series of patients with FL, behavior, and in these cases, a wait-and-watch strategy might be
it was shown that p53 mutations are not associated with transforma- justified. Recent work demonstrates that indolent MCL cases can
tion to DLBCL.57 be identified either by gene expression profiling or by staining for
The importance of the tumor microenvironment in the clin- the transcription factor SOX11, as these MCL samples are charac-
ical course of FL has been demonstrated in a recent gene expression terized by the absence of SOX11.63
profiling study of 191 FL patient samples (Fig 3).58 The length of Deregulation of cell cycle is the characteristic pathogenetic hall-
survival could be predicted at the time of diagnosis by measuring mark of MCL (Fig 4). Accordingly, the most important biologic prog-
two gene expression signatures consisting of genes known to be nostic factor determined in several studies is the proliferation rate,
expressed in normal immune cells. The immune-response 1 signa- determined either by the number of mitoses or the Ki67 staining
ture was associated with favorable outcome and reflects a mixture index, with cases having a high proliferation index being associated
of immune cells that is enriched for T cells. In contrast, the genes in with adverse outcome.64 These results were confirmed by a large gene
the immune-response 2 signature, which is associated with poor expression profiling study that showed the prognostic impact of a gene
overall survival, reflect an immune infiltrate that is enriched for expression– based proliferation signature.65
macrophages and/or dendritic cells.58 Several studies based either Cell cycle deregulation is caused by different genetic abnor-
on immunohistochemistry or reverse transcription polymerase malities (Fig 4). MCLs are characterized by the chromosomal
chain reaction confirmed the finding that the composition of the translocation t(11;14) (q13;q32) that juxtaposes the CCND1 gene
microenvironment strongly influences prognosis of patients to the IgH locus, leading to deregulation and overexpression of the
with FL.59,60 cell cycle regulator cyclin D1. Cyclin D1, which is normally not
In summary, despite the fact that our understanding of the inter- expressed at high levels in normal B cells, plays an important role in
action between follicular lymphoma and normal immune cells is still cellular proliferation by propelling cells from the G1 to S phase of
rudimental, it seems conceivable that the composition and the nature the cell cycle. Cyclin D1 forms heterodimers with the cyclin-
of the immune cells could have an impact on response to immune dependent kinases CDK4 and CDK6, thereby forming active ki-
modulatory therapies such as monoclonal antibodies. nase complexes.66 These complexes phosphorylate and inactivate

1808 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 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- Another pathogenetic feature of MCLs is the deregulation of
press its protective effect on cell cycle progression (Fig 4). Equally DNA damage response, as evidenced by the high number of chro-
important, Cyclin D1/CDK4/6 complexes bind to p27kip1, an mosomal aberrations and the occurrence of tetraploid karyotypes
inhibitor of cyclin E/CDK2 complexes. This sequestration of in some aggressive MCL cases.72 In a large fraction of MCL sam-
p27kip1 allows the cyclin E/CDK2 complexes to promote S-phase ples, mutations and deletions of the ataxia-telangiectasia mutated
entry by phosphorylation of Rb.66 (ATM) gene, which plays an important role in the cellular response
A small fraction of MCL samples seems to be cyclin D1 to DNA damage, are detectable.73 Additionally, alterations in other
negative. Interestingly, these cases are histologically indistin- elements of the DNA response pathway have been detected in
guishable from cyclin D1–positive samples and additionally MCL. p53 mutations occur in roughly 15% of MCL samples and
have the same gene expression signature. These cases seem to are associated with poor prognosis.74 p53 is upregulated in re-
express either cyclin D2 or cyclin D3 to substitute for the lacking sponse to cellular stress as DNA damage, resulting in cell cycle
cyclin D1 expression.67 arrest or apoptosis. Alternative mechanisms to inactivate p53 are
Other genetic aberrations that deregulate cell cycle regulation are high levels of MDM2 expression in a small fraction of MCL cases or
homozygous deletions affecting p16INK4a and p14ARF on chromosome loss of p14ARF, which stabilizes p53 by inhibition of MDM2-
9p21, which have been described in a substantial proportion of aggres- mediated ubiquitination and degradation.70
sive MCL cases.68 p16INK4a inhibits the interaction between CDK4 and Several recent studies identified additional genetic aberrations
⫺6 and cyclinD1 and thereby controls the phosphorylation and inac- that might play a role in the biology of MCL. A combined approach of
tivation of Rb.65 Some MCLs have amplification and/or overexpres- high-resolution gene expression and copy number profiling identified
sion of BMI1, which acts as a transcriptional repressor of the p16INK4A CUL4A, ING1, and MCPH1 to be potentially involved in dysregula-
locus.69 Additionally, CDK4 was found to be amplified and overex- tion of proliferation and DNA damage response.75 Additionally, the
pressed in a fraction of highly aggressive MCLs (Fig 4).70 At last, the Rb PI3k–mammalian target of rapamycin (mTOR) pathway seems to be
gene, has been found to be inactivated by deletions in MCL cases with involved in the pathogenesis of MCL, as phosphorylation and activa-
a high proliferation rate.71 tion of AKT is present in the majority of proliferative MCL cases.76

www.jco.org © 2011 by American Society of Clinical Oncology 1809

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

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

grade and high-grade gastric MALT lymphomas. 26. Bea S, Zettl A, Wright G, et al: Diffuse large
REFERENCES Blood 95:1032-1038, 2000 B-cell lymphoma subgroups have distinct genetic
14. Ramiro AR, Jankovic M, Eisenreich T, et al: profiles that influence tumor biology and improve
1. Fugmann SD, Lee AI, Shockett PE, et al: The AID is required for c-myc/IgH chromosome translo- gene-expression-based survival prediction. Blood
RAG proteins and V(D)J recombination: Complexes, cations in vivo. Cell 118:431-438, 2004 106:3183-3190, 2005
ends, and transposition. Annu Rev Immunol 18:495- 15. Lenz G, Nagel I, Siebert R, et al: Aberrant 27. Schmidlin H, Diehl SA, Nagasawa M, et al:
527, 2000 immunoglobulin class switch recombination and Spi-B inhibits human plasma cell differentiation by
2. Rajewsky K: Clonal selection and learning in switch translocations in activated B cell-like diffuse repressing BLIMP1 and XBP-1 expression. Blood
the antibody system. Nature 381:751-758, 1996 large B cell lymphoma. J Exp Med 204:633-643, 112:1804-1812, 2008
3. Muramatsu M, Kinoshita K, Fagarasan S, et al: 2007 28. Joos S, Otano-Joos MI, Ziegler S, et al: Primary
Class switch recombination and hypermutation re- 16. A clinical evaluation of the International Lym- mediastinal (thymic) B-cell lymphoma is characterized by
quire activation-induced cytidine deaminase (AID), a phoma Study Group classification of non-Hodgkin’s gains of chromosomal material including 9p and amplifi-
potential RNA editing enzyme. Cell 102:553-563, lymphoma: The Non-Hodgkin’s Lymphoma Classifi- cation of the REL gene. Blood 87:1571-1578, 1996
2000 cation Project. Blood 89:3909-3918, 1997 29. Joos S, Kupper M, Ohl S, et al: Genomic
4. Goossens T, Klein U, Kuppers R: Frequent 17. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct imbalances including amplification of the tyrosine
occurrence of deletions and duplications during so- types of diffuse large B-cell lymphoma identified by gene kinase gene JAK2 in CD30⫹ Hodgkin cells. Cancer
matic hypermutation: Implications for oncogene expression profiling. Nature 403:503-511, 2000 Res 60:549-552, 2000
translocations and heavy chain disease. Proc Natl 18. Rosenwald A, Wright G, Chan WC, et al: The 30. Xiao C, Srinivasan L, Calado DP, et al: Lym-
Acad Sci U S A 95:2463-2468, 1998 use of molecular profiling to predict survival after phoproliferative disease and autoimmunity in mice
5. Manis JP, Tian M, Alt FW: Mechanism and chemotherapy for diffuse large-B-cell lymphoma.
with increased miR-17-92 expression in lympho-
control of class-switch recombination. Trends Im- N Engl J Med 346:1937-1947, 2002
cytes. Nat Immunol 9:405-414, 2008
munol 23:31-39, 2002 19. Rosenwald A, Wright G, Leroy K, et al: Mo-
31. Morin RD, Johnson NA, Severson TM, et al:
6. Bakhshi A, Jensen JP, Goldman P, et al: lecular diagnosis of primary mediastinal B cell lym-
Somatic mutations altering EZH2 (Tyr641) in follicu-
Cloning the chromosomal breakpoint of t(14;18) phoma identifies a clinically favorable subgroup of
lar and diffuse large B-cell lymphomas of germinal-
human lymphomas: Clustering around JH on chro- diffuse large B cell lymphoma related to Hodgkin
center origin. Nat Genet 42:181-185, 2010
mosome 14 and near a transcriptional unit on 18. lymphoma. J Exp Med 198:851-862, 2003
32. Su GH, Chen HM, Muthusamy N, et al: De-
Cell 41:899-906, 1985 20. Savage KJ, Monti S, Kutok JL, et al: The
fective B cell receptor-mediated responses in mice
7. Raghavan SC, Swanson PC, Wu X, et al: A molecular signature of mediastinal large B-cell lym-
lacking the Ets protein, Spi-B. EMBO J 16:7118-
non-B-DNA structure at the Bcl-2 major breakpoint phoma differs from that of other diffuse large B-cell
7129, 1997
region is cleaved by the RAG complex. Nature lymphomas and shares features with classical
33. Davis RE, Brown KD, Siebenlist U, et al:
428:88-93, 2004 Hodgkin lymphoma. Blood 102:3871-3879, 2003
8. Migliazza A, Martinotti S, Chen W, et al: Constitutive nuclear factor kappaB activity is re-
21. Turner CA Jr, Mack DH, Davis MM: Blimp-1, a
Frequent somatic hypermutation of the 5⬘ noncod- novel zinc finger-containing protein that can drive the quired for survival of activated B cell-like diffuse
ing region of the BCL6 gene in B-cell lymphoma. maturation of B lymphocytes into immunoglobulin- large B cell lymphoma cells. J Exp Med 194:1861-
Proc Natl Acad Sci U S A 92:12520-12524, 1995 secreting cells. Cell 77:297-306, 1994 1874, 2001
9. Wang X, Li Z, Naganuma A, et al: Negative 22. Tam W, Gomez M, Chadburn A, et al: Muta- 34. Lam LT, Wright G, Davis RE, et al: Coopera-
autoregulation of BCL-6 is bypassed by genetic tional analysis of PRDM1 indicates a tumor suppres- tive signaling through the signal transducer and
alterations in diffuse large B cell lymphomas. Proc sor role in diffuse large B-cell lymphomas. Blood activator of transcription 3 and nuclear factor-
Natl Acad Sci U S A 99:15018-15023, 2002 107:4090-4100, 2006 {kappa}B pathways in subtypes of diffuse large
10. Pasqualucci L, Neumeister P, Goossens T, et 23. Pasqualucci L, Compagno M, Houldsworth J, B-cell lymphoma. Blood 111:3701-3713, 2008
al: Hypermutation of multiple proto-oncogenes in et al: Inactivation of the PRDM1/BLIMP1 gene in 35. Lam LT, Davis RE, Wright G, et al: Small
B-cell diffuse large-cell lymphomas. Nature 412:341- diffuse large B cell lymphoma. J Exp Med 203:311- molecule inhibitors of IkB-kinase are selectively
346, 2001 317, 2006 toxic for subgroups of diffuse large B cell lymphoma
11. Liu M, Duke JL, Richter DJ, et al: Two levels 24. Iqbal J, Greiner TC, Patel K, et al: Distinctive defined by gene expression profiling. Clin Cancer
of protection for the B cell genome during somatic patterns of BCL6 molecular alterations and their Res 11:28-40, 2005
hypermutation. Nature 451:841-845, 2008 functional consequences in different subgroups of 36. Ngo VN, Davis RE, Lamy L, et al: A loss-of-
12. Bergsagel PL, Chesi M, Nardini E, et al: Pro- diffuse large B-cell lymphoma. Leukemia 21:2332- function RNA interference screen for molecular tar-
miscuous translocations into immunoglobulin heavy 2343, 2007 gets in cancer. Nature 441:106-110, 2006
chain switch regions in multiple myeloma. Proc Natl 25. Lenz G, Wright GW, Emre NC, et al: Molecular 37. Rawlings DJ, Sommer K, Moreno-Garcia ME:
Acad Sci U S A 93:13931-13936, 1996 subtypes of diffuse large B-cell lymphoma arise by The CARMA1 signalosome links the signalling ma-
13. Nardini E, Aiello A, Giardini R, et al: Detection distinct genetic pathways. Proc Natl Acad Sci U S A chinery of adaptive and innate immunity in lympho-
of aberrant isotype switch recombination in low- 105:13520-13525, 2008 cytes. Nat Rev Immunol 6:799-812, 2006

1810 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
 Biology of NHL

38. Lenz G, Davis RE, Ngo VN, et al: Oncogenic ways of clonal evolution in follicular lymphomas. survival in mantle cell lymphoma. Cancer Cell 3:185-
CARD11 mutations in human diffuse large B cell Genes Chromosomes Cancer 39:195-204, 2004 197, 2003
lymphoma. Science 319:1676-1679, 2008 53. Gaidano G, Hauptschein RS, Parsa NZ, et al: 66. Sherr CJ, McCormick F: The RB and p53
39. Davis RE, Ngo VN, Lenz G, et al: Chronic Deletions involving two distinct regions of 6q in pathways in cancer. Cancer Cell 2:103-112, 2002
active B-cell-receptor signalling in diffuse large B-cell B-cell non-Hodgkin lymphoma. Blood 80:1781-1787, 67. Fu K, Weisenburger DD, Greiner TC, et al:
lymphoma. Nature 463:88-92, 2010 1992 Cyclin D1-negative mantle cell lymphoma: A clinico-
40. Compagno M, Lim WK, Grunn A, et al: 54. Cheung KJ, Shah SP, Steidl C, et al: Genome- pathological study based on gene expression profil-
Mutations of multiple genes cause deregulation of wide profiling of follicular lymphoma by array compar- ing. Blood 106:4315-4321, 2005
NF-kappaB in diffuse large B-cell lymphoma. Na- ative genomic hybridization reveals prognostically 68. Pinyol M, Hernandez L, Cazorla M, et al:
ture 459:717-721, 2009 significant DNA copy number imbalances. Blood 113: Deletions and loss of expression of p16INK4a and
41. Kato M, Sanada M, Kato I, et al: Frequent 137-148, 2009
p21Waf1 genes are associated with aggressive vari-
inactivation of A20 in B-cell lymphomas. Nature 55. O’Shea D, O’Riain C, Taylor C, et al: The
ants of mantle cell lymphomas. Blood 89:272-280,
459:712-716, 2009 presence of TP53 mutation at diagnosis of follicular
1997
42. Novak U, Rinaldi A, Kwee I, et al: The NF- lymphoma identifies a high-risk group of patients
69. Beà S, Tort F, Pinyol M, et al: BMI-1 gene
{kappa}B negative regulator TNFAIP3 (A20) is inacti- with shortened time to disease progression and
amplification and overexpression in hematological
vated by somatic mutations and genomic deletions poorer overall survival. Blood 112:3126-3129, 2008
malignancies occur mainly in mantle cell lympho-
in marginal zone lymphomas. Blood 113:4918-4921, 56. Pinyol M, Cobo F, Bea S, et al: P16(INK4a)
2009 gene inactivation by deletions, mutations, and hy- mas. Cancer Res 61:2409-2412, 2001
43. Schmitz R, Hansmann ML, Bohle V, et al: permethylation is associated with transformed and 70. Hernández L, Bea S, Pinyol M, et al: CDK4 and
TNFAIP3 (A20) is a tumor suppressor gene in Hodg- aggressive variants of non-Hodgkin’s lymphomas. MDM2 gene alterations mainly occur in highly pro-
kin lymphoma and primary mediastinal B cell lym- Blood 91:2977-2984, 1998 liferative and aggressive mantle cell lymphomas
phoma. J Exp Med 206:981-989, 2009 57. Davies AJ, Lee AM, Taylor C, et al: A limited with wild-type INK4a/ARF locus. Cancer Res 65:
44. Monti S, Savage KJ, Kutok JL, et al: Molecular role for TP53 mutation in the transformation of 2199-2206, 2005
profiling of diffuse large B-cell lymphoma identifies follicular lymphoma to diffuse large B-cell lym- 71. Pinyol M, Bea S, Pla L, et al: Inactivation of
robust subtypes including one characterized by host phoma. Leukemia 19:1459-1465, 2005 RB1 in mantle cell lymphoma detected by
inflammatory response. Blood 105:1851-1861, 2005 58. Dave SS, Wright G, Tan B, et al: Prediction of nonsense-mediated mRNA decay pathway inhibi-
45. Lenz G, Wright G, Dave SS, et al: Stromal survival in follicular lymphoma based on molecular tion and microarray analysis. Blood 109:5422-
gene signatures in large-B-cell lymphomas. N Engl features of tumor-infiltrating immune cells. N Engl 5429, 2007
J Med 359:2313-2323, 2008 J Med 351:2159-2169, 2004 72. Ott G, Kalla J, Ott MM, et al: Blastoid variants
46. Hanahan D, Folkman J: Patterns and emerg- 59. Farinha P, Masoudi H, Skinnider BF, et al: Analysis of mantle cell lymphoma: Frequent bcl-1 rearrange-
ing mechanisms of the angiogenic switch during of multiple biomarkers shows that lymphoma-associated ments at the major translocation cluster region and
tumorigenesis. Cell 86:353-364, 1996 macrophage (LAM) content is an independent predictor tetraploid chromosome clones. Blood 89:1421-
47. Schraders M, de Jong D, Kluin P, et al: Lack of of survival in follicular lymphoma (FL). Blood 106:2169- 1429, 1997
Bcl-2 expression in follicular lymphoma may be 2174, 2005 73. Schaffner C, Idler I, Stilgenbauer S, et al:
caused by mutations in the BCL2 gene or by ab- 60. Byers RJ, Sakhinia E, Joseph P, et al: Clinical Mantle cell lymphoma is characterized by inactiva-
sence of the t(14;18) translocation. J Pathol 205: quantitation of immune signature in follicular lym- tion of the ATM gene. Proc Natl Acad Sci U S A
329-335, 2005 phoma by RT-PCR-based gene expression profiling. 97:2773-2778, 2000
48. Leich E, Salaverria I, Bea S, et al: Follicular Blood 111:4764-4770, 2008
74. Greiner TC, Moynihan MJ, Chan WC, et al:
lymphomas with and without translocation t(14;18) 61. Banks PM, Chan J, Cleary ML, et al: Mantle
p53 mutations in mantle cell lymphoma are associ-
differ in gene expression profiles and genetic alter- cell lymphoma: A proposal for unification of morpho-
ated with variant cytology and predict a poor prog-
ations. Blood 114:826-834, 2009 logic, immunologic, and molecular data. Am J Surg
nosis. Blood 87:4302-4310, 1996
49. McDonnell TJ, Deane N, Platt FM, et al: Pathol 16:637-640, 1992
75. Hartmann EM, Campo E, Wright G, et al:
Bcl-2-immunoglobulin transgenic mice demonstrate 62. Campo E, Raffeld M, Jaffe ES: Mantle-cell
Pathway discovery in mantle cell lymphoma by
extended B cell survival and follicular lymphoprolif- lymphoma. Semin Hematol 36:115-127, 1999
eration. Cell 57:79-88, 1989 63. Fernàndez V, Salamero O, Espinet B, et al: integrated analysis of high-resolution gene expres-
50. Roulland S, Navarro JM, Grenot P, et al: Follic- Genomic and gene expression profiling defines in- sion and copy number profiling. Blood 116:953-961,
ular lymphoma-like B cells in healthy individuals: A dolent forms of mantle cell lymphoma. Cancer Res 2010
novel intermediate step in early lymphomagenesis. J 70:1408-1418, 2010 76. Rudelius M, Pittaluga S, Nishizuka S, et al:
Exp Med 203:2425-2431, 2006 64. Bosch F, Lopez-Guillermo A, Campo E, et al: Constitutive activation of Akt contributes to the
51. Cheung KJ, Johnson N, Affleck J, et al: Ac- Mantle cell lymphoma: Presenting features, re- pathogenesis and survival of mantle cell lymphoma.
quired TNFRSF14 mutations in follicular lymphoma sponse to therapy, and prognostic factors. Cancer Blood 108:1668-1676, 2006
are associated with inferior prognosis. Cancer Res 82:567-575, 1998 77. Cerchietti LC, Yang SN, Shaknovich R, et al: A
70:9166-9174, 2010 65. Rosenwald A, Wright G, Wiestner A, et al: The peptomimetic inhibitor of BCL6 with potent anti-
52. Höglund M, Sehn L, Connors JM, et al: Identi- proliferation gene expression signature is a quanti- lymphoma effects in vitro and in vivo. Blood 113:
fication of cytogenetic subgroups and karyotypic path- tative integrator of oncogenic events that predicts 3397-3405, 2009

■ ■ ■

www.jco.org © 2011 by American Society of Clinical Oncology 1811

Downloaded from ascopubs.org by 190.168.40.113 on September 27, 2017 from 190.168.040.113

Copyright © 2017 American Society of Clinical Oncology. All rights reserved.