Table 1 IGH/K rearrangements in different B-cell malignancies
From: Next-generation sequencing for MRD monitoring in B-lineage malignancies: from bench to bedside
B-cell malignancies | Origin | IG rearrangements | Clonal evolution | Citation | ||
|---|---|---|---|---|---|---|
V(D)J rearrangement | SHM and CSR | Other features | ||||
ALL | Pre-B cells | IGH V-D-J usage: VH usage: VH3 > VH1 > VH2, VH4 (most frequent: VH6-1, VH1-2. VH3-11, VH3-13, VH3-15) D usage: D2 > D3 > D6 (Most frequent: D2-21 in pro-B ALL)JH usage: JH4, JH6 | Low-mutated or unmutated | High frequency of unproductive IGH rearrangements due to the continuously active recombinase enzyme | Continuing rearrangements process or independent new rearrangements | |
IGL V-J usage: Vκ usage: Vκ1 > Vκ2 | No age-associated genotype pattern | Clonal selection during treatment | ||||
Various IG gene characteristics at diagnosis have no prognostic value | Oligoclonality of IGH at relapse is less frequent | |||||
Monoclonal IGH rearrangements/Major clones/clone with complete V-D-J recombination are stable | ||||||
MCL | Naïve mature B cells or memory-like B cells | IGH V-D-J usage: VH usage: VH3 > VH4 > VH1 > VH2 (Most frequent: VH3-21, VH3-23, VH4-34, VH1-8, VH4-59) D usage: D3 > D6, D1 (Most frequent: D3-22, D3-3) JH usage: JH4 > JH6 | Minimally mutated or unmutated | Two molecular subtypes: conventional (cMCL) and leukemic non-nodal (nnMCL | Information unavailable | |
IGL V-J usage: Vλ usage: Vλ1, Vλ2, Vλ3 (Most frequent: Vλ2-14) Vκ usage: Most frequent: Vκ3, Vκ3-20 | t(11;14)q(13,32), the CCND1/IGH rearrangement | MCL express IgL-λ more frequently due to more K-de rearrangements | ||||
Stereotyped HCDR3 VH4-34/D2-2/JH6 VH4-34/D1-26/JH6 VH3-21/D3-9/JH6 VH3-21/D3-9/JH4 VH3-21/D6-6/JH6 + Vλ3-19/Jλ2 | CCND2/CCND3 translocation with IGK/IGL | Highly restricted IG gene repertoire with stereotyped HCDR3 imply a role for antigen-driven selection in the oncogenesis | ||||
Stereotyped LCDR3: Vλ3-19/Jλ2-1 Vλ2-14/Jλ2-1 Vλ2-14/Jλ3-1 Vκ3-10/Jκ2-1 Vκ3-10/Jκ4-1 | ||||||
CLL | B cells in GC | IGH V-D-J usage: VH usage: VH3 > VH1, VH4 (Most frequent: VH1-69, VH4-34, VH3-23, VH3-30, VH1-2) | Differences of prognosis based on SHM level: Unmutated (U-CLL): SHM < 2%, pre-GC, worse survival Mutated (M-CLL): SHM > 2%, GC and post-GC, better survival | SHM in hotspots | Intra-clonal diversification within CLL is limited | |
Stereotyped HCDR3: VH1-69/D3-16/JH3 + VκA27 VH1-69/D3-3/JH6 + Vλ3-9 VH3-21/D3-3/JH6 + Vλ2-14 VH3-21 + Vλ3-21 VH4-34 + Vκ2-30 VH4-39/D6-13/JH5 + Vκ(D)1–39 VH1-3/D6-19/JH4 + Vκ(D)1–39 VH1-2/D2-2/JH6 + Vκ(D)1–39 VH3-23/D3-3/JH6 VH3-23/D4-23/JH3 | Antigen selection | |||||
Stereotyped BCR, and most major subsets concerned unmutated with high conservation across the entire HCDR3 | ||||||
Satellite subsets to major subsets | ||||||
Different ontogenetic trajectories for stereotyped and non-stereotyped cases | ||||||
Autoreactive specificities | ||||||
DLBCL | B cells in GC | IGH V-D-J usage: VH usage: VH1 > VH3 > VH4 > VH2 (Most frequent: VH1-2, VH4-34, VH3-23, VH4-39, VH1-69, VH5-51, VH3-21) D usage: D3, D2 (Most frequent: D3-22, D3-10) JH usage: JH4, JH6 | Ongoing SHM or mutated | Monoclonality is associated with poor prognostics | Two modes of clonally-related relapse: the early divergent mode and the late divergent mode | |
IGH D-J usage: D2 (Most frequent: D2-2) | Characteristics of canonical SHM | GCB or non-GCB type DLBCL shows no association with clonal status of IG rearrangements | No correlation between DLBCL subtypes and relapse clonal evolution | |||
Stereotyped HCDR3: VH1-69/D3-10/JH6 VH1-69/D3-3/JH6 VH4-34/D3-22/JH2 | High IGL SHM with poorer prognosis | Shorter IGH-CDR3 is associated with better OS and PFS | Clonally-unrelated relapse tends to occur later after initial lymphoma | |||
The degree of SHM in GCB is higher than in ABC | Ongoing IGH SHM correlates with poorer survival | Selective pressure including treatment selection before relapse and antigen selection during malignant transformation | ||||
SHM occurs in FR regions | Abnormal IgMκ/IgMλ ratio predicts worse prognosis | |||||
The overexpression of BACH2 is associated with ongoing SHM of IGHV and more frequently happens in GCB subtype | ||||||
FL | B cells in GC | IGH V-D-J usage: VH usage: VH3 > VH4 > VH1 (Most frequent: VH1-18, VH3-48, VH3-15, VH3-34, VH3-23, VH3-30, VH3-21) D usage: D2, D3 (Most frequent: D3-10, D3-22, D3-3) JH usage: JH4 | Ongoing SHM or highly mutated | Biased VH usage indicates antigen participation in lymphomagenesis | ISFL: an intermediate stage between FL and t(14;18) B cells | |
In tFL (compared with non-GCB DLBCL): VH1 is underrepresented and VH3 is overrepresented | t(14;18)(q32;q21), the BCL2/IGH rearrangement | The VH3-48 gene is associated with the risk of histological transformation (HT) | Transformation of FL to DLBCL more frequently occurs via divergent evolution from a putative common progenitor | |||
Significant mutations in either HCDR3 or LCDR3 but not both | The N-gly sites within IGHV region | The transformation was achieved through HT and involved a clonal relationship between FL and the more aggressive disease | ||||
The natural course of FL is not linear | Patients with higher number of subclones have a longer PFS | |||||
BCR signalling is functional throughout FL tumour evolution | ||||||
MM | Memory B cells | 1.IGH V-D-J usage VH usage: VH3 > VH4 > VH1 (Most frequent: VH3-30, VH3-23, VH5-51, VH1-69, VH3-9, VH4-31; Absent: VH4-34) D usage: D3, D2 (Most frequent: D3-3, D3-10) JH usage: JH4, JH6 | Highly mutated CDR3 of either IGH or IGL with no intra-clonal variation | Higher SHM level is associated with an improved survival rate | Intra-clonal diversity of CDR3 sequences was rare | |
1.IGL V-J usage: Vκ usage: Vκ1, Vκ3, Vκ2 (Most frequent: Vκ2-30, Vκ1(D)-33) Jκ usage: Jκ4, Jκ2 Vλ usage: No clear preference Jλ usage: Jλ2, Jλ3 | Most cases are class-switched | CDR3 composition of MM disease clone resembled the normal immunoglobulin repertoire | All dominant clonal sequences were stable over time | |||
Translocation involving IGH gene (14q32) | The success rate of IGK assay in λ-restricted samples is higher than in κ-restricted ones | Dominant clonal CDR3 sequences identified at baseline are reliable biomarker for MRD tracking | ||||
Less SHM in clonal Vκ rearrangement from λ-restricted clones compared with κ-restricted clones | ||||||