Page 952 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 56 Conventional and Molecular Cytogenomic Basis of Hematologic Malignancies 835

reside in the germinal center of normal lymph nodes. In a study of According to the WHO classification, three BL variants are rec-
85 reactive lymph nodes of healthy individuals 14% were found to ognized: endemic, sporadic, and immunodeficiency-associated BL. In
contain high levels of t(14;18) by Q-PCR. These studies provide contrast, many cases of Burkitt-like lymphoma (a separate WHO
evidence that FLLCs consistently accumulate within the germinal entity), lack BL translocations but do exhibit increased MYC
center, as nonproliferating, early precursor cells that have not acquired expression.
other genetic events leading to FL transformation. 28 High-throughput RNA sequencing has revealed acquired somatic
GEP has revealed a distinct pattern associated with an indolent mutations in the CCND3 gene in 38% of sporadic BL cases. This is
form of FL (median survival 11.1 years) and a more aggressive form an important gene in cell cycle progression and 70% of these patients
(median survival 3.9 years), indicating that these different conditions acquire mutations affecting the transcription factor TCF3 or its nega-
may represent distinct stages in the evolution of FL. Detailed genetic tive regulator ID3. In an extended study mutations in the ID3 gene
analyses have confirmed that a single mechanism driving the trans- were detected in 50% of all IGH-MYC translocation-positive sporadic
formation of FL to DLBCL does not exist, rather several discrete BL and these mutations were found to be rare in other IG-MYC-
mechanisms are operational, including alterations of cell-cycle control positive lymphomas. These findings suggest that disruption of ID3
(mutations and deletions of cyclin-dependent kinase, CDKN2A/B), function may be a key mechanism in the pathogenesis of BL. More-
MYC rearrangements and impairment of the DNA damage response over, recurrent mutations in TP53, SMARCCA4 (chromatin modu-
(loss of TP53 and/or CDKN2A/B). NGS has shown that each is lating complex gene), and DDX3X (chromatin modulating complex
associated typically with between 20 and 200 small somatic muta- gene) may contribute to BL evolution.
tions. At least 21 different tumor suppressor genes are altered in FL Approximately 35% of patients with DLBCL and approximately
at frequencies between 2% and 86%, suggesting that FL requires 5% to 10% of patients with FL have rearrangements in the BCL6
multiple collaborative genomic events acquired over many years. gene which resides at 3q27. Translocation and dysregulation of BCL6
Three translocations, all affecting the MYC gene at 8q24, have gene represents a key mechanism of transformation of DLBCL.
been recognized in BL. In 80% of patients a reciprocal translocation Chromosomal rearrangements of the BCL6 locus occur in about 35%
t(8;14)(q24; q32) is observed between the MYC gene and the IGH to patients with DLBCL, and at least 33 different partners have
locus (Figs. 56.56 and 56.57). In the remainder of patients, the been described as participating in these rearrangements (http://
reciprocal translocation t(8;22)(q24;q11) or t(2;8)(p12;q24) occurs atlasgeneticsoncology.org/) (see Fig. 56.55E). The most frequent
juxtaposing MYC to one of the light-chain loci (κ on 2p12 and λ on chromosomal band partners are 2p13, 4p13, 6p22, 7p12, 8q24,
22q11). The t(8;14) translocation was originally described in Epstein- 13q14, 14q32, 18p11.2, and 22q11. These translocations juxtapose
Barr virus (EBV) tumor cells obtained from patients in Africa (see the coding domain of BCL6 downstream to heterologous promoters
Fig. 56.56B–C). Variant translocations involving MYC with a variety derived from different chromosomal partners, leading to dysregulated
of other non-IG loci subsequently have been reported. In most expression of an intact protein by preventing its downregulation
patients with sporadic BL, the breakpoints on 8q24.1 are located on during postgerminal center differentiation. The BCL6 5′ sequences
5′ end of the coding region of MYC gene. By contrast, in most cases are targeted by multiple point mutations in over 70% of cases. Most
of endemic BL and in non-IG translocations, the MYC breakpoints of the breakpoints in 3q27 occur within a 10-kb region. The fact that
are at the 3′ end. As a result of the translocation, control of MYC is the 3q27 region is affected in different lymphomas, irrespective of
lost, and the intact protein is constitutively expressed throughout the the translocation partner chromosomes, strongly suggests that altera-
cell cycle. tions of BCL6, and not the reciprocal loci, are important in the
Although MYC-IGH translocations are sine qua non for the pathogenesis. The alterations in 3q27 are small so most can be
diagnosis of BL, they are not restricted to BL because they also occur detected with PCR-based assays, or FISH. BCL6 functions as a
in other forms of lymphoma, such as DLBCL (see later), plasma cell transcriptional repressor of genes containing its binding sites; there-
myeloma, ALL, MCL, and CLL. fore the mechanism responsible for the malignant phenotype is
MYC regulates almost 15% of human genes. The MYC gene can transcriptional deregulation.
function as both a transcriptional activator and a transcriptional Over the past decade NGS has enhanced our understanding of
repressor. MYC forms a heterodimer with MYC associated factor X the complex multiple pathways by which DLBCL develops. Approxi-
(MAX). MYC-MAX heterodimer binds to the E-box consensus mately 30% of patients with DLBCL harbor mutations and/or
sequence (CACATG) and serves as a platform for other proteins deletions inactivating CREBBP and more rarely EP300, two acetyl-
involved in chromatin remodeling and transcriptional regulation. transferases that modify lysine residues on both histone and nonhis-
MYC represses genes when it is not bound directly to DNA, but tone nuclear proteins, and therefore modulate the activity of a large
instead is recruited by the MIZ1 transcription factor, which in turn number of DNA-binding transcription factors. About one-third of
recruits DNA methyltransferase (DNMT3) and histone deacetylase patients with DLBCL harbor mutations in the MLL2 gene, which
3 (HDAC3) which alter chromatin configuration making it less broadly affects chromatin structure. Inactivating mutations of both
accessible. CREBBP and MLL2 have also been observed in FL (49% and about
An increased level of constitutive MYC syntheses in leukemic 89%, respectively). Gain-of-function somatic mutations in MEF2B
disorders is found not only as a result of a translocation but also as transcription factor gene are observed in 10% to 15% of patients
a result of mutations and amplification of MYC (see Fig. 56.57). with DLBCL. Other genetic lesions include loss-of function/deletions
Approximately 65% of BL are associated with MYC point mutations. of FBX011 (4%), which causes BCL6 dysregulation by impairing
As mentioned previously, overexpression of MYC protein is linked to proteosomal-mediated degradation of the BCL6 protein. Mutations
amplification of MYC genes reported in plasma cell leukemia, AML, and deletions of TP53 remain an important genetic lesion in about
CML, and T-cell lymphoma. MYC both directly and indirectly 20% of patients with DLBCL, including those resulting from trans-
activates CCND2 and cyclin dependent kinases and downregulates formation from FL.
cell cycle inhibitors, promoting the transition from G0 to S phase. t(14;15)(q32;q11–13) occur in 3% to 4% of DLBCL, which
MYC has a role in the formation and maintenance of germinal results in fusion of the BCL8 gene on chromosome 15 to the V H
centers. segment of the IGH locus. The most common secondary abnormali-
The most common secondary change associated with t(8;14) in ties are trisomies of chromosomes 3, 5, 7q, 11, 12p, 18q, and Xq,
BL is duplication of the long arms of chromosome 1, and these were which are observed in greater than 10% of cases. Amplification of
associated with disease progression. A common duplicated region of REL, MYC, BCL2, GLI, CDK4, and MDM2 genes are most fre-
93 kb at 1q21.2 has been defined by FISH studies. A rare complex quently associated with advanced-stage disease. The most frequent
BL karyotype is shown in Fig. 56.56. Rearrangements of MYC can monosomies include chromosomes 13, 14, and 15. A complex
now be detected in nondividing cells as well as in paraffin-embedded karyotype may have an adverse impact on prognosis.
lymph node biopsies using a very sensitive interphase FISH assay for The use of modern molecular studies identified two major sub-
t(8;14). groups in DCLBC: activated B cell–like DLBCL (ABC-DCLBC)