Page 1384 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 76

ORIGIN OF NON-HODGKIN LYMPHOMA

Matthew S. McKinney and Sandeep S. Dave

Over the past two decades, discoveries in basic immunology and the activation-induced cytidine deaminase (AID) expression and SHM
pathogenesis of malignancies have significantly advanced our under- are favored because of protection from apoptosis. Through this
standing of the origin of lymphoid neoplasms. These diseases have mechanism, protective antibodies are produced at the risk of exposing
been reexamined and grouped based on recurrent chromosomal antigen-stimulated B cells to genetic lesions caused by the molecular
rearrangements, histologic patterns, and gene expression profiles. The machinery utilized to create V(D)J recombination and SHM. Many
multiple revisions to the World Health Organization’s classification NHLs exhibit translocations of driver oncogenes to highly active Ig
schemes for lymphomas reflect this progress. As with other cancers, loci, implying that recombination events intended to produce high-
lymphoma development is dependent upon acquisition of mutations, affinity antibodies are misdirected and instead produce immortalized
DNA copy number changes, recurrent cytogenetic rearrangements, B cells representing stages of B-cell development. Furthermore, muta-
and epigenetic dysregulation of gene expression involving oncogenic tions in oncogenes or tumor suppressors frequently occur in a pattern
and tumor suppressor pathways. Many of these derangements occur consistent with SHM at these loci. When considered together with
as a result of disordered genetic recombination and somatic hyper- the recurrent chromosomal rearrangements noted in NHL, this
mutation (SHM) events intended to support adaptive immunity. confirms the notion that these neoplasms stem from mature B cells
Also, analysis of molecular features of lymphomas compared with that have entered (or are poised to enter) GCs.
normal lymphocyte compartments provides clues to the events Subsets of NHL recapitulate this pattern of normal B-cell differ-
driving their pathogenesis. entiation at the histologic, molecular, and genomic levels and serve
An evolving understanding of the steps involved in lymphoid as a template for the classification of these diseases. This template can
development has provided further insights into the development be applied to the entire spectrum of B-cell neoplasms, suggesting that
of this diverse group of malignancies because most non-Hodgkin NHLs form as a result of genetic alterations developed along this
lymphomas (NHLs) reflect stages of lymphoid development. The process. B-cell differentiation must be carefully choreographed at the
application of gene expression profiling (GEP) and massively parallel molecular and genomic level because the expression of the RAG genes
high-throughput sequencing, as well as a better appreciation of the and AID cause DNA strand breaks and put the nascent lymphocyte
contribution of microRNAs (miRNAs) and epigenetic alterations to at risk of oncogene overexpression and tumor suppressor deletion.
lymphoma pathogenesis, have shed new light on the mechanisms Moreover, a coordinated regulation of gene expression is required to
underlying lymphomagenesis. Correlation of these findings with the allow such genomic revision without triggering reflexive, protective
clinical outcomes has further refined prediction of outcome, and has apoptotic pathways and to allow appropriate B-cell differentiation.
suggested targets for novel therapies. GC B cells highly express BCL6, and its functions are critically
This chapter reviews the most common NHL subtypes, focusing important to regulation of cell survival and differentiation. Targets of
on common B cell lymphoma subtypes, with regard to classification BCL6 also include cell cycle regulators (p21, p27) and TP53, which
using prevailing views regarding genetic or genomic classification of may overall work to facilitate cell cycle progression in the face of
these disorders. Additionally, insights regarding pathogenesis, prog- ongoing AID-mediated DNA strand breaks. BCL6 also represses
nosis, and possible therapeutic targets gleaned from genomic PRDM1/Blimp1 and serves to prevent plasmacytic differentiation.
approaches are discussed. Plasma cell differentiation is mediated by upregulation of IRF4 and
nuclear factor kappa-B (NFκB), which establish characteristic regula-
tory programs.
OVERVIEW OF B-CELL LYMPHOMAS Genetic lesions altering these pathways are found recurrently in
NHL. BCL6 rearrangements occur in diffuse large B-cell lymphoma
Greater than 85% of NHL cases have a B-cell phenotype. With (DLBCL) and other lymphomas, and constitutively active NFκB
rare exception, B-cell lymphomas represent immortalized, “frozen” signaling is associated specifically with aggressive phenotypes of
stages of B-cell development and the underlying molecular features DLBCL. Translocations and or mutations of BCL2, which is expressed
of B-cell tumors reflect biologic features found in analogous normal at very low levels in GCs, occur in almost all follicular lymphomas
B-cell compartments. Understanding factors governing regulation of (FLs) and illustrate the dangers of aberrant recombination events in
B-cell compartments that mirror B-cell NHL subtypes is thus crucial the GCs because BCL2 translocation appears to be a primary event
to comprehending the driving forces behind lymphoma development in the formation of these tumors. Recent analyses of whole genome/
(Fig. 76.1). exome/transcriptome sequencing data have confirmed the frequent
The goal of early B-cell development is to produce mature B cells presence of these genetic lesions and have illuminated other pathways
expressing surface immunoglobulin M (IgM) that can efficiently driving lymphomagenesis. In GC-derived B cell lymphomas, muta-
recognize cognate antigen. After this is accomplished, B cells develop tions in EZH2, a member of the polycomb group (PcG), occur fre-
along pathways involving germinal center (GC), mantle, and mar- quently. In these tumors, EZH2 mutations result in aberrant histone
ginal zones in lymphoid organs where they encounter antigens in methylation with resultant dysregulated control of gene expression
association with activated antigen-presenting cells (APCs). Differen- and result in GC hyperplasia in mouse models. This process appears
tiation of mature B cells into plasma cells after SHM is the final step to enhance lymphomagenesis due to an acquired inability of GC B
in B-cell development and is critical to the development of effective cells to differentiate and appropriately complete maturation and thus
humoral immunity. Antibody diversity is accomplished through the become transformed in a state of reflecting GC B cells (Fig. 76.2). A
process of somatic V(D)J recombination at the pro–B cell stage via similar role for GC regulation has been defined for genes in the
recombinase activating genes (RAG1 and RAG2) followed by traffick- sphingosine-1-phosphate receptor2 (S1PR-2) signaling pathway.
ing to GCs where they proliferate rapidly with dividing times of Genes encoding mediators of this pathway such as S1PR2, P2RY8
6 to 8 hours. High-affinity B-cell clones produced in part via and GNA13 are frequently mutated in GC B-derived lymphomas and

1230