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186 Part IV: Molecular and Cellular Hematology Chapter 13: Cytogenetics and Genetic Abnormalities 187

cells in the cerebrospinal fluid. These same clinical characteristics are with a t(8;14)(q24.2;q32.3) have either small noncleaved cell or DLBCL
associated with lymphoblastic lymphoma, another T-cell malignancy. (Chap. 98). Band 14q32.3, the location of IGH is frequently involved in
translocations in B-cell neoplasms (approximately 70 percent). In con-
CHRONIC LYMPHOCYTIC LEUKEMIA trast, a large proportion of T-cell neoplasms are characterized by rear-
rangements that involve 14q11.2, 7q34, or 7p14, the locations of the T-cell
The chromosomal abnormalities associated with chronic lymphocytic receptor genes (Chap. 104). Gene expression profiling has proven useful
leukemia (CLL) have been delineated through the use of FISH (Chap. in distinguishing unique genetic subtypes of lymphoma. 79
92). When conventional cytogenetic techniques are used, only 50 per- The t(8;14) is characteristic of both endemic and nonendemic
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cent of CLL patients have detectable chromosomal abnormalities. The Burkitt tumors, as well as Epstein-Barr virus (EBV)–negative and
most common abnormality is trisomy 12 (20 to 60 percent), followed EBV-positive tumors (see Fig. 13–5; Chap. 102). Moreover, the t(8;14)
by structural abnormalities of 13q and 14q (see Table 13–4). How- has also been observed in other lymphomas, particularly small non-
ever, when FISH analysis is used to study specific abnormalities, chro- cleaved cell (non-Burkitt) and large cell immunoblastic lymphomas,
mosomal abnormalities can be detected in greater than 80 percent of HIV-associated Burkitt lymphoma (100 percent) and HIV-related
patients. The most frequent chromosomal changes seen by FISH are: DLBCL (30 percent). Two other variant translocations also occur in
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loss or deletion of 13q (55 percent); deletion of 11q, the location of the Burkitt lymphoma, t(2;8)(p12;q24.2) and t(8;22)(q24.2;q11.2). All three
ATM gene (18 percent); trisomy of 12q (16 percent); deletion of 17p, translocations involve chromosome band 8q24.2. These same translo-
the location of the TP53 gene; and deletion of 6q (6 percent). The LOH cations have been seen in some patients with B-cell ALL. The t(8;14)
affecting 17p frequently coincides with the TP53 mutations (7 percent) involves a break within the IGH locus on chromosome 14, and a break
and can be detected by CMA. Patient survival correlates with cyto- either 5′ or within the MYC gene on chromosome 8, and relocates the
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genetic subtype, with a shorter median survival observed in patients MYC coding exons to chromosome 14. MYC is a transcription factor
with 17p (32 months) or 11q (79 months) deletions, than in those with that plays a critical role in a number of cellular processes including
no detectable abnormality (111 months), trisomy of 12q (114 months), DNA replication, proliferation, and apoptosis; its oncogenic properties
or −13/del(13q) (133 months). Two micro-RNA genes (miR-16–1 and are a result of its constitutive expression.
miR-15a) are possible target genes in the 13q14.3 region. FISH probes Between 70 and 90 percent of follicular lymphomas (Chap. 99) and
capable of detecting the deletions of 11q, 13q, and 17p, trisomy 12, 20 percent of DLBCL have the t(14;18) (see Fig. 13–6), in which the
and immunoglobulin heavy chain (IGH) translocations are commer- BCL2 gene at 18q21.3 is juxtaposed to the IGH J segment, leading to
cially available, and facilitate the application of risk-adapted treatment the deregulated expression of BCL2. Common secondary abnormali-
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strategies. ties include −7, +18, and del(6q). Other malignancies that overexpress
The prognosis of patients with CLL is also determined by two other BCL2, but do not harbor the t(14;18), include hairy cell leukemia and
molecular abnormalities: the status of the IGH variable region and the CLL. The BCL2 gene encodes a 26-kDa mitochondrial membrane pro-
expression level of CD38 (Chap. 92). Patients whose CLL cells express tein that functions to increase cell survival through antiapoptosis and
IGH genes containing somatic mutations have a 24-year median sur- preventing programmed cell death.
vival compared to only 6 to 8 years in those patients who do not have The t(11;14) (q13.3;q32.3) is observed in virtually all cases of man-
somatic IGH gene mutations. This simple grouping of patients based tle cell lymphoma (Chap. 100), 3 percent of myeloma (Chap 107), and
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on the mutation status of the IGH gene may reflect the fact that CLL up to 20 percent of prolymphocytic leukemias (Chap. 92). 82,83 Many
cells that have few or no IGH mutations also often contain chromoso- cases also have deletions or point mutations of the ATM gene (11q22.3).
mal aberrations that confer a poor prognosis, for example deletions of Mantle cell lymphomas are currently regarded as a poor prognostic
11q or 17p, or trisomy 12, whereas CLL cells with IGH mutations often group with a median survival from diagnosis of 3 years. This translo-
contain deletions of 13q, which confer a more favorable clinical course. cation results in the activation of the cyclin D1 (CCND1) gene by the
Unfortunately, testing for somatic mutations in the IGH gene is not cur- IGH gene (J region). The CCND1 gene is located 100 to 130 kb away
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rently commercially available. ZAP-70, an enzyme normally expressed from the breakpoint on 11q13.3. The D-type cyclins act as growth fac-
in T lymphocytes and critical for T-cell activation, is upregulated in tor sensors, causing cells to go through the restriction start point of the
CLL cells that contain unmutated IGH genes, conferring a poor prog- cell cycle at G and committing them to divide via phosphorylation and
1
nosis (Chap. 92). Patients whose CLL cells have mutated IGH and lack inactivation of RB1.
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expression of ZAP-70 and CD38, a membrane protein with signaling The BCL6 gene was cloned from the recurring breakpoint at 3q27
activity have the longest treatment-free period after initial diagnosis. 77 in cells characterized by a t(3;22)(q27;q11.2), t(3;14)(q27;q32.3) or,
T-cell CLL and large granular lymphocytic leukemia are uncom- rarely, t(2;3)(p12;q27). BCL6 rearrangements occur in 40 percent of
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mon disorders in which the malignant lymphocytes have a T-cell immu- DLBCLs and, in some series, up to 10 percent of follicular lymphomas.
nophenotype. Rearrangements involving band 14q11.2 with or without The translocations lead to the truncation of the BCL6 gene within the
an accompanying break in 14q32.1 have been reported in T-CLL as well first exon or the first intron, substitution of its promoter sequences with
as in T-cell lymphomas (see Table 13–4). The most common is inv(14) an IG promoter, and deregulated expression. The BCL6 gene product
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(q11.2q32.1). is a 96-kDa POZ/Zn finger, nuclear protein that acts as a potent tran-
scriptional repressor. It is predominantly expressed in the B-cell lin-
LYMPHOMA eage, particularly in mature B cells, and may suppress genes involved in
lymphocyte activation, differentiation, cell cycle arrest, and apoptosis.
Cytogenetic analyses of patients with lymphoma have demonstrated that Somatic mutations have been identified in the 5′ regulatory regions of
more than 90 percent of cases are characterized by clonal chromosomal BCL6 in approximately 20 percent of DLBCLs without translocations
abnormalities and, more importantly, many of the recurring abnormalities leading to deregulation of BCL6, suggesting that overexpression of
correlate with histology and immunophenotype (see Table 13–4; Chaps. BCL6 is more broadly involved than initially recognized. 84
95 and 96). For example, the t(14;18) is observed in a high proportion of Extranodal marginal zone B-cell lymphomas of mucosa-associated
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follicular small cleaved cell lymphomas (70 to 90 percent), most patients lymphoid tissue (MALT lymphoma) are comprised of several genetic
with a t(3;22)(q27;q11.2) or t(3;14)(q27;q32.3) have DLBCL, and patients subgroups, one characterized by trisomy 3 plus other abnormalities

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