Telomeric IGH Losses Detectable by Fluorescence in Situ Hybridization in Chronic Lymphocytic Leukemia Reflect Somatic VH Recombination Events

Abstract

Chromosomal translocations affecting the immunoglobulin loci, particularly immunoglobulin heavy chain (IGH) genes complex at 14q32, are a hallmark of B cell malignancies.1,2 They usually result in deregulated expression of involved oncogenes (eg, BCL1, CMYC, and PAX5) juxtaposed to the regulatory elements of IGH. As some of these translocations are associated with specific subtypes of mature B cell lymphoma and have prognostic significance, their detection is of clinical importance. In daily practice, IGH translocations have been routinely analyzed by fluorescence in situ hybridization (FISH) using either a common LSI IGH dual-color, break-apart rearrangement assay or dual-color, dual-fusion oncogene-specific probe, such as LSI IGH/CCND1, IGH/ BCL2, and IGH/CMYC.The IGH-mediated translocations are relatively rare in B cell chronic lymphocytic leukemia (CLL), [3][4][5] which is the most common form of leukemia in adults and shows a highly variable clinical course. The CLL cells display a phenotype of mature activated B lymphocytes expressing CD19, CD5, and CD23 and having reduced levels of membrane IgM, IgD, and CD79b. The co-expression of CD19 and CD5, however, is also characteristic for mantle cell lymphoma (MCL), which, in contrast to CLL, is usually an aggressive disease hallmarked by the t(11;14)(q13; q32)/IGH-CCND1 rearrangement. Differential diagnosis between CLL and leukemic MCL is sometimes challenging. 5 Given that up to 30% of MCL cases have immunophenotypic features characteristic of B-CLL, albeit usually with atypical, pleomorphic morphology, 6 immunophenotyping alone is insufficient to exclude a diagnosis of MCL. Therefore, in the Belfast City Hospital (Belfast, Northern Ireland) all suspected CLL cases have been routinely examined by rapid interphase FISH with the LSI IGH/CCND1 assay to identify t(11;14)-positive MCL cases, in addition to examination for CLL typical cytogenetic aberrations. During this analysis, a subset of CLL

Comparison of <b><i>IGH </i></b>Profile Signals Using t(4;14) and <b><i>IGH</i></b> Break-Apart Probes by FISH in Multiple Myeloma

“…A gain of IGH signals could possibly signify trisomy 14, which is considered as a rare event in MM [Kumar et al, 2012]. However, nonspecific patterns not related to IGH rearrangements due to cohybridization of IGH green signals in 15q11 and 16p11.2 are also well described [Wlodarska et al, 2007].…”

“…No falsenegative signal for t(4; 14) was identified, even if associations between IGH deletions and IGH translocations are well described in studies and were found in 22.7% of newly diagnosed MM [He et al, 2015]. IGH loss or partial deletion may be part of a physiological event or part of an oncogenic process of B-lineage cells [Fink et al, 2005;Pospisilova et al, 2007;Wlodarska et al, 2007]. When they are part of an oncogenic process, they may be considered as additional chromosomal aberrations and associated with a decrease of overall survival [Leiba et al, 2016].…”

Array-based karyotyping in chronic lymphocytic leukemia (CLL) detects new unbalanced abnormalities that escape conventional cytogenetics and CLL FISH panel

“…37 ). On the other hand, the detected deletions tend to associate with additional chromosomal changes, such as trisomy 12 and IgVH unmutated status 38 . Both cases with 3´IgH deletion were unmutated, as well as 7 out of 10 cases with 5´IgVH deletion, and in all cases additional changes were observed.…”

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays

“…The presence of one fusion signal and one single-color signal (either red or green) was considered as indicative of deletion of part of the Ig gene, a phenomenon reflecting physiologic rearrangement of the IgH gene. 26 Cut-off for positivity. To establish the cutoff, we used 10 cases of reactive tonsil, spleen and thymus tissues arranged in the five TMAs plus two reactive lymph nodes on two separate slides.…”