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188 Part IV: Molecular and Cellular Hematology Chapter 13: Cytogenetics and Genetic Abnormalities 189

(60 percent), and another by the t(11;18)(q21.2;q21.3)(25 to 50 percent) gene). The t(4;14)(p16.3;q32.3) is noted in approximately 15 percent of
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and its variants (Chap. 101). Of note is that the t(11;18) is not observed in patients and deregulates the expression of the fibroblast growth factor
primary large B-cell gastric lymphoma. The t(11;18) results in the fusion receptor 3 gene (FGFR3) translocated to the der(14), and the WHSC1/
of the apoptosis-inhibitor gene BIRC3 (API2), to a novel gene at 18q21.3, MMSET domain remaining on the der(4) chromosomes. The t(14;16)
MALT1, whose product activates the nuclear factor κB (NFκB) pathway. (q32.3;q23), noted in 5 percent of cases, results in the overexpression
A number of recurring chromosomal abnormalities have been of the MAF transcription factor gene. Cyclin D3 overexpression occurs
recognized in T-cell leukemias and lymphomas (see Table 13–4; in the context of the t(6;14)(p21.1;q32.3), observed in 4 percent of
Chap. 104). Similar to B-cell neoplasms, in which rearrangements fre- patients. The translocation partners for the remaining 10 to 15 percent
quently involve the chromosomal bands containing the immunoglob- of myeloma cases are currently unknown. The t(4;14) and t(14;16) are
ulin gene loci, T-cell neoplasms often have rearrangements involving both associated with a poor clinical outcome, whereas the t(11;14) con-
band 14q11.2, the site of the T-cell receptor α-chain (TRA) and δ-chain fers a favorable prognosis. Translocations involving unknown partners
(TRD) genes or, less often, one of two regions of chromosome 7 (7q34 confer an intermediate prognosis.
and 7p14) to which the T-cell receptor β-chain (TRB) and γ-chain Chromosome 1 abnormalities are prevalent in multiple myeloma,
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(TRG) genes have been localized, respectively. These translocations frequently resulting in both gain of 1q and loss of 1p, and are associated
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result from aberrant V-D-J recombination events. With few exceptions, with a shorter survival. Furthermore, gene expression profiling studies
the involved gene on the partner chromosome encodes a transcription that identified a high-risk disease signature noted a significant enrich-
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factor, whose expression is deregulated or activated as a result of the ment of genes located on chromosome 1. For this reason, it is now
rearrangement (see Table 13–4). As a consequence of a chromosomal recommended that a comprehensive FISH testing panel for multiple
rearrangement that brings an oncogene under the controlling influence myeloma include detection of chromosome 1 abnormalities, particu-
of promoters and enhancers that are active in T-cell receptor synthesis, larly using probes for 1q.
T-cells may gain a proliferative advantage, resulting in malignant clonal Additional events occur with disease progression, including muta-
expansion. tions of NRAS and KRAS, MYC deregulation, and epigenetic altera-
A distinctive subtype of lymphoma, namely, anaplastic large cell tions. Activating mutations of NRAS or KRAS have been identified in
lymphoma (ALCL) is characterized by a young age at presentation, and monoclonal gammopathy (approximately 5 percent), and at a higher
skin and/or lymph node infiltration by large, often bizarre lymphoma frequency in myeloma (30 to 40 percent); but the frequency may be
cells, which preferentially involve the paracortical areas and lymph node higher in patients who relapse (80 percent). Several genes are silenced
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sinuses (Chap. 98). The majority of such tumors express one or more through aberrant promoter hypermethylation in both monoclonal
T-cell antigens, a minority express B-cell antigens, and some express both gammopathy and myeloma, including DAPK1 (67 percent), SOCS1,
T- and B-cell antigens (the null phenotype). A reciprocal translocation, CDKN2B (p15), and CDKN2A (p16). 83
t(2;5)(p23.2;q35.1), t(1;2)(q25;p23), or variant rearrangement involving
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