Clonal T-cell abnormalities can originate from a variety of molecular genetic events. Translocations can result in a fusion of (parts of) different genes if the breakpoint is within the affected genes. Upregulation of gene expression also can result, if the breakpoint is located outside the coding region. This can expose a gene to the enhancing effects of other genes and regulatory sequences that are in close proximity due to the translocation. Anaplastic large cell lymphoma, which is a T-cell or null-cell lymphoma, is associated with translocation t(2;5) (p23;q35). This translocation is characterized by a fusion between the nucleophosmin (NPM) gene on chromosome 5 and the anaplastic lymphoma kinase (ALK) gene on chromosome 2.3,4 It is the most common cytogenetic abnormality in noncutaneous forms of anaplastic large cell lymphoma and the only recurring translocation that is routinely tested for in mature T-cell lymphomas. ALK can fuse with other genes as well, including TPM3 at 1p21, TFG at 3q21, ATIC at 2q35, CTLC at 17q23, and MSN at Xq11-12.4,5
In addition to gene translocations, allelic loss of a tumor suppressor gene can contribute to the development of lymphoma. An example is loss of function of the P15 and P16 genes on the short arm of chromosome 9.6 Allelic loss and gene silencing due to promoter methylation were identified in both early and advanced stages of Sezary syndrome and mycosis fungoides. Cytogenetic anomalies, including deletions and inversions on the long arms of chromosomes 8, 11, and 14, are associated with T-cell prolymphocytic leukemia. However, due to the variation in gene fusion
Figure 33-1. Various stages of T-cell development and an overview of the order of TCR gene rearrangements. (TdT, terminal deoxynucleotidyl transferase.)
sites, none of these translocations is currently analyzed routinely at the molecular level.
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