Immune Gene Rearrangements: Unique Signatures for Tracing Physiological Lymphocytes and Leukemic Cells

Abstract

The tremendous diversity of the human immune repertoire, fundamental for the defense against highly heterogeneous pathogens, is based on the ingenious mechanism of immune gene rearrangements. Rearranged immune genes encoding the immunoglobulins and T-cell receptors and thus determining each lymphocyte’s antigen specificity are very valuable molecular markers for tracing malignant or physiological lymphocytes. One of their most significant applications is tracking residual leukemic cells in patients with lymphoid malignancies. This so called ‘minimal residual disease’ (MRD) has been shown to be the most important prognostic factor across various leukemia subtypes and has therefore been given enormous attention. Despite the current rapid development of the molecular methods, the classical real-time PCR based approach is still being regarded as the standard method for molecular MRD detection due to the cumbersome standardization of the novel approaches currently in progress within the EuroMRD and EuroClonality NGS Consortia. Each of the molecular methods, however, poses certain benefits and it is therefore expectable that none of the methods for MRD detection will clearly prevail over the others in the near future.

Insights into IGH clonal evolution in BCP-ALL: frequency, mechanisms, associations, and diagnostic implications

“…MRD monitoring utilizing clone-specific sequences of the uniquely rearranged and edited gene segments is widely used to assess therapy response after induction and consolidation therapy, which has crucial prognostic importance in BCP-ALL patients ( 17 – 23 ). High-throughput sequencing (HTS)-based marker identification and MRD monitoring offers the benefit of providing additional information on background repertoire including minor accompanying clones, which may reflect clonal evolution [reviewed in ( 24 )].…”

Cell‐free DNA for detection of clonal B cells in diffuse large B cell lymphoma by sequencing

“…Specific gene mutations in cfDNA have been investigated by targeted sequencing or digital PCR 18–20 and, more recently, also targeted and whole‐genome sequencing, 21 proving that such investigation could be useful for response evaluation, prognostics and diagnostics. Currently, one of the most widely applied targets for determining measurable residual disease in clonal B cell malignancies is the rearranged immunoglobulin heavy chain (IgH) genes 22,23 . These unique clonal rearrangements can be detected by allele‐specific oligonucleotide PCR or next‐generation sequencing (NGS) 22,24,25 .…”

“…Currently, one of the most widely applied targets for determining measurable residual disease in clonal B cell malignancies is the rearranged immunoglobulin heavy chain (IgH) genes. 22,23 These unique clonal rearrangements can be detected by allele-specific oligonucleotide PCR or next-generation sequencing (NGS). 22,24,25 One study investigated clonotypes in plasma to monitor DLBCL after infusion of chimeric antigen receptor T cells and showed that plasma could be used for prediction of patient outcomes.…”

Dominant T-cell Receptor Delta Rearrangements in B-cell Precursor Acute Lymphoblastic Leukemia: Leukemic Markers or Physiological γδ T Repertoire?

“…It is unclear if these rearrangements originate from leukemic cells or represent clonally expanded benign T-cell populations, most probably belonging to the γδ T-cell fraction, a minor subset of T cells with potent antileukemic activity, 9 as αβ T cells regularly delete their TRD loci in the process of the formation of TRA rearrangements. 3 To address this question, we have systematically analyzed TRD rearrangement profiles in diagnostic samples of 839 BCP-ALL patients (Figure 1A; 645 bone marrow aspirates, 193 blood samples, and 1 ascites) enrolled within the German Multicenter Adult Acute Lymphoblastic Leukemia (GMALL) Registry or the GMALL 08/2013 trial between 02/2016 and 05/2020. All patients gave informed consent to using residual material for research purposes.…”

“…Both phenomena are presumably a consequence of aberrant, persisting recombination processes in malignant immature lymphoid cells. 3 Depending on patients age and ALL subtype, a considerable number of B-cell precursor ALL (BCP-ALL) harbor TR cross-lineage rearrangements. 4 For instance, TR delta ( TRD ) gene rearrangements occur in 40%–90% of BCP-ALL as cross-lineage rearrangements, especially in ALL cells arrested in early stages of differentiation, and are mostly restricted to incomplete TRDV2-TRDD3, TRDD2-TRDD3 rearrangements, or to combined TRDV-TRAJ recombinations, which are rare in normal lymphoid cells.…”