From the Guidelines
Yes, IGH rearrangement can contribute to the development of NHL. IGH rearrangements are normal processes in B-cell development that create diverse antibodies, but when these rearrangements go awry, they can lead to oncogenic events. In B-cell NHL specifically, chromosomal translocations involving the IGH locus on chromosome 14 are common pathogenic mechanisms. Notable examples include the t(14;18) translocation in follicular lymphoma, which juxtaposes the BCL2 gene with IGH regulatory elements, and the t(8;14) translocation in Burkitt lymphoma, which places the MYC oncogene under IGH control. These translocations cause dysregulated expression of these genes, promoting lymphoma development through increased cell proliferation and decreased apoptosis.
Key Points
- IGH rearrangement analysis is also clinically useful as a diagnostic tool to determine B-cell clonality in suspected lymphomas and can help distinguish malignant lymphoid proliferations from reactive processes 1.
- The exact mechanism of Richter’s transformation, which is the transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (DLBCL), is not well understood but has been associated with molecular characteristics of the patients’ CLL and their prior CLL-directed therapies 1.
- IGHV sequences can be used to define the clonal relation between DLBCL and CLL, which is important for determining the treatment approach for Richter’s transformation 1.
- Treatment regimens for Richter’s transformation include therapies used in DLBCL, such as R-CHOP, and alloSCT is recommended for patients with clonally-related Richter’s transformation with an available donor and sufficient fitness 1. Some of the key evidence for this includes:
- A 2021 study published in the Annals of Oncology, which provided guidelines for the diagnosis, treatment, and follow-up of chronic lymphocytic leukemia, including the role of IGH rearrangements in the development of NHL 1.
- A 2019 study published in the Journal of the National Comprehensive Cancer Network, which discussed the molecular characteristics associated with the risk of developing Richter’s transformation, including unmutated IGHV status and cytogenetic abnormalities 1.
From the Research
IGH Rearrangement and NHL
- IGH rearrangements have been identified in approximately 50% of non-Hodgkin B-cell lymphomas (NHLs) and are correlated to clinically relevant subgroups 2, 3.
- The detection rate of IGH rearrangements varies with the technique used, with fluorescence in situ hybridization (FISH) techniques being more sensitive than conventional cytogenetics 2, 3.
- Specific types of IGH rearrangements, such as t(14;18)(q32;q21) and t(11;14)(q13;q32), are associated with particular subtypes of NHL, including follicular lymphoma and mantle cell lymphoma 2, 3.
Mechanism of IGH Rearrangement in NHL
- IGH rearrangements involve the immunoglobulin heavy chain gene (IGH) at 14q32 and can result in the formation of fusion genes that contribute to lymphomagenesis 4.
- Cryptic or masked IGH rearrangements can occur in some cases of NHL, and may involve novel partner chromosomes 4.
- The identification of IGH rearrangements is important for understanding the molecular mechanisms involved in the genesis of lymphoma and for developing targeted therapies 2, 3.
Clinical Implications of IGH Rearrangement in NHL
- IGH rearrangements can be used as a diagnostic marker for certain subtypes of NHL, and may also have prognostic significance 2, 3.
- The presence of IGH rearrangements may influence the choice of treatment for patients with NHL, with some studies suggesting that rituximab-based therapies may be more effective in patients with certain types of IGH rearrangements 5, 6.
- Further research is needed to fully understand the clinical implications of IGH rearrangements in NHL and to develop more effective therapies for patients with these genetic abnormalities.