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1234 Part VII Hematologic Malignancies

of DLBCLs cannot be classified using this system and have been the most common rearrangement seen in DLBCL and occurs in about
deemed unclassified DLBCL. There are thousands of genes that differ 30% of both the ABC and GCB subtypes. An oncogenic phenotype
between these subtypes at the GEP level, which is a magnitude similar results from this genetic rearrangement through upregulation of the
to that seen between acute myeloid and lymphoblastic leukemias BCL6 gene. Additional mutations in the transcriptional regulatory
that have profoundly different mechanisms of origin and natural program of BCL6 may also occur with alternative translocation.
histories. Notably, BCL6 translocations appear to not be sufficient for lymphoma
GC B DLBCLs express a characteristic spectrum of genes and formation as evidenced by mice bearing t(3;14) translocations that
exhibit evidence of ongoing AID-mediated SHM as well as a histo- develop NHL at a low rate. BCL2 translocations occur in a minority
logic phenotype consistent with GC origin. BCL6 and LMO2 are of GCB DLBCLs but are not seen in the ABC phenotype; this mirrors
both important to the transcriptional program of GCs and are com- the situation in FL, in which BCL2 overexpression is associated with
mensurately overexpressed in GCB DLBCLs. Conversely, PRDM1 is disordered GC transit. MYC rearrangements additionally occur in
downregulated by BCL6, which results in decreased PRDM1 activity DLBCL (~10% to 15% of cases), sometimes with rearrangements of
in GCs, and GCB DLBCLs display a similar pattern. Histologically, BCL2, BCL6, or both. These tumors, sometimes termed double-hit
GCB DLBCLs are characterized by CD10 expression and lack of lymphomas, display an aggressive phenotype seemingly intermediate
IRF4 expression. Evaluation of Ig loci within GCB DLBCLs has also between BL and DLBCL.
revealed evidence of ongoing SHM, which is further evidence that Oncogenic mutations and areas of chromosomal amplification or
GCB DLBCLs reflect the biology of normal GC B cells and that deletion also appear important in the pathogenesis of DLBCL.
dysregulation of pathways involved in GC formation might lead to Upregulation of c-REL occurs in about 20% of GCB tumors through
this subset of DLBCL. amplification of the 2p locus. Amplification of MYC and BCL2 may
Alternatively, the ABC subtype of DLBCL expresses a post-GC also occur through this mechanism. TP53 mutations and SHM of
phenotype but appears trapped just before differentiation into plasma other loci, including PIM1, BCL6, and MYC, also appear to contrib-
cells. ABC DLBCLs are characterized by downregulation of many ute to lymphoma formation and progression. Mutations in CARD11
GC genes, including BCL6 and LMO2, and by expression of genes causing constitutive NFκB activation have been described in a subset
associated with activated B cells and plasma cells. One of the hall- of both ABC and GCB DLBCLs and appear to drive oncogenesis in
marks of the ABC DLBCL phenotype is upregulation of NFκB. these tumors. Overall, the patterns of gene mutation and recurrent
NFκB is a transcription factor that targets a number of gene programs cytogenetic abnormalities add further complexity to the classification
governing cell proliferation, immortality, and angiogenesis within of DLBCLs.
NHLs. The effectors of NFκB signaling exist in inactive form in the The genetic mutational landscapes of genes involved in DLBCL
cytosol and require signaling either through MAPK/ERK (mitogen- pathogenesis have also been reported. Most recently, several groups
activated protein kinase/extracellular signal-regulated kinase) signal- have reported analyses of whole-genome, exome, or transcriptome
ing (the canonical NFκB pathway) or through ligation of data from the application of massively parallel sequencing in DLBCLs.
CD40–LTbR–BAFF-R (B-cell activating factor receptor), which These studies have identified hundreds of novel mutations in DLBCL
results in phosphorylation of the inactive complex and translocation and have further defined patterns of mutational overlap through
of either the p50–RelA or p52–Rel B complexes to the nucleus and studies of mutual exclusivity (Fig. 76.5). Interestingly, some of the
subsequent transcription of target genes. In ABC DLBCL cell lines, molecular features of lymphoma subtypes such as activation of the
a signaling complex involving CARD11, BCL10, and MALT1 (the NFκB signaling pathway identified through gene expression profiling
CBM complex) constitutively activates NFκB signaling and selective been shown to correlate with specific mutations in DLBCL cancer
knock-down of any of the components of this complex using RNAi genes. Inactivating mutations of PRDM1 and mutation in genes
or small molecule inhibitors is lethal to ABC cell lines. Interestingly, regulating NFκB signaling (TNFAIP3, MYD88, CARD11) have been
a few GCB cell lines also demonstrate activation of NFκB and noted in ABC DLBCL subtypes. CD79B and BCL2 have also been
mutations in the NFκB pathway, which might confer sensitivity to found to harbor mutations in DLBCL and other NHLs. A series that
inhibition of this pathway in those tumors. The mechanisms by performed RNA sequencing on 127 NHL samples (including 83
which DLBCLs acquire and maintain constitutive NFκB activity are DLBCL tumors) found 651 coding single nucleotide variants
still being elucidated and may provide insights into the origin and (cSNVs), many of which were not previously documented in malig-
into possible treatments for this entity. nancies. Truncating deletions in tumor suppression genes (TP53,
Primary mediastinal B-cell lymphoma (PMBL) represents a dis- TNFRSF14, CREBBP) were among the most significantly mutated
tinct subset of patients that have sometimes been classified as DLBCL. genes and other heavily mutated genes not previously known to be
PMBL was originally identified based on the clinical characteristics involved in DLBCL pathogenesis (including MLL2, BTG1, EZH2
of the disease. Patients with PMBL are generally young (third or and GNA13). MLL2 contained cSNVs in 26% of tumors and most
fourth decades of life), predominantly women, and present with a often occurred as a heterozygous defect, and sometimes multiple
large mediastinal mass; outcomes with chemoimmunotherapy for mutations occurred in trans fashion. MLL2 functions as a H3K4-
PMBL are generally superior to those with other subtypes of DLBCL. specific methyltransferase responsible for regulation of transcription
GEP studies revealed that PMBL can be clearly delineated from ABC of developmental genes. Ostensibly, MLL2 might serve to deregulate
and GCB, subtypes. Indeed, by gene expression, PMBL appears genes involved in differentiation or development and act in conjunc-
similar to Hodgkin lymphoma with many shared features in both tion with other oncogenes to facilitate NHL. Other groups have
diseases, including the expression of CD30 (Fig. 76.4). Both diseases confirmed mutations in MLL2 and other genes (CREBBP/EP300)
also express genes associated with JAK (Janus-activated kinase)–STAT that coordinate chromatin acetylation, leading to the hypothesis that
(signal transducer and activator of transcription) signaling as well as mutations in histone-modifying genes lead to DLBCL and other
targets of the NFκB pathway. NHLs. Further work is needed to dissect the mechanism(s) by which
the various molecular lesions in individual tumors cause lymphoma
Molecular Pathogenesis of Diffuse Large formation and this will perhaps also improve our understanding of
normal lymphocyte biology while providing new tools for lymphoma
B-Cell Lymphoma diagnosis and treatment.

Investigation of the molecular landscape of DLBCL has revealed a set
of recurrent cytogenetic and molecular abnormalities associated with The Tumor Microenvironment and Diffuse
pathogenesis. Chromosomal translocations involving BCL6, BCL2, Large B-Cell Lymphoma
and MYC (v-myc myelocytomatosis viral oncogene homolog) occur
frequently in DLBCL, and these translocations appear to be specific to The complexities of antigen presentation and recognition and regula-
cell-of-origin phenotype. 3q27 rearrangement with Ig gene partners is tion of B-cell proliferation that occur in GCs suggest that the