Clinical significance of productive immunoglobulin heavy chain gene rearrangements in childhood acute lymphoblastic leukemia

Abstract

We analyzed the CDR3 region of 80 children with B-cell acute lymphoblastic leukemia (B-ALL) using the ImMunoGeneTics Information System and JOINSOLVER. In total, 108 IGH@ rearrangements were analyzed. Most of them (75.3%) were non-productive. IGHV@ segments proximal to IGHD-IGHJ@ were preferentially rearranged (45.3%). Increased utilization of IGHV3 segments IGHV3-13 (11.3%) and IGHV3-15 (9.3%), IGHD3 (30.5%), and IGHJ4 (34%) was noted. In pro-B ALL more frequent were IGHV3-11 (33.3%) and IGHV6-1 (33.3%), IGHD2-21 (50%), IGHJ4 (50%), and IGHJ6 (50%) segments. Shorter CDR3 length was observed in IGHV@6, IGHD7, and IGHJ1 segments, whereas increased CDR3 length was related to IGHV3, IGHD2, and IGHJ4 segments. Increased risk of relapse was found in patients with productive sequences. Specifically, the relapse-free survival rate at 5 years in patients with productive sequences at diagnosis was 75% (standard error [SE] ±9%), whereas in patients with non-productive sequences it was 97% (SE ±1.92%) (p-value =0.0264). Monoclonality and oligoclonality were identified in 81.2% and 18.75% cases at diagnosis, respectively. Sequence analysis revealed IGHV@ to IGHDJ joining only in 6.6% cases with oligoclonality. The majority (75%) of relapsed patients had monoclonal IGH@ rearrangements. The preferential utilization of IGHV@ segments proximal to IGHDJ depended on their location on the IGHV@ locus. Molecular mechanisms occurring during IGH@ rearrangement might play an essential role in childhood ALL prognosis. In our study, the productivity of the rearranged sequences at diagnosis proved to be a significant prognostic factor.

Characterization of clonal immunoglobulin heavy (IGH) V-D-J gene rearrangements and the complementarity-determining region in South Indian patients with precursor B-cell acute lymphoblastic leukemia

“…However, our study results differed from previous reports, which have shown that 40% and 21% of IGH rearrangements result in productive rearrangements [1420]. However, our results correlate with a study of 108 IGH sequences from 80 children with precursor B-ALL, which revealed that 75.3% of them were unproductive [22]. …”

Next-generation sequencing for MRD monitoring in B-lineage malignancies: from bench to bedside

“…ALL is considered to originate from pre-B cells, which are aberrantly blocked at the transition to immature B cells. This mechanism explains the unmutated or low-mutated status due to lack of SHM, the high frequency of unproductive IGH rearrangements due to continuously active recombinase enzyme, and the initiation of IGK/IGL rearrangements that go against allelic exclusion rules due to improper in-frame selection [ 40 , 41 , 47 , 59 ]. Clonal evolution can’t be ignored in ALL and likely occurs by continuing rearrangement processes (successive VH to DJH or secondary rearrangements) [ 40 , 41 ] and selection pressure mediated by treatments [ 60 ].…”

“…This mechanism explains the unmutated or low-mutated status due to lack of SHM, the high frequency of unproductive IGH rearrangements due to continuously active recombinase enzyme, and the initiation of IGK/IGL rearrangements that go against allelic exclusion rules due to improper in-frame selection [ 40 , 41 , 47 , 59 ]. Clonal evolution can’t be ignored in ALL and likely occurs by continuing rearrangement processes (successive VH to DJH or secondary rearrangements) [ 40 , 41 ] and selection pressure mediated by treatments [ 60 ]. Measurements of the IG gene repertoire exhibited biased VH usage toward VH3 and VH1 families, most frequently involving the VH6-1, VH1-2, VH3-11, VH3-13, and VH3-15 segments.…”

“…During adaptive immune responses, B cells react to antigenic stimulation and rapidly proliferate, forming clones with the same V(D)J pattern and possible intraclonal diversity at the nucleotide level attributed to SHM. Similarly, after malignant transformation at a certain time point during B cell differentiation triggered by either activation of oncogenes or inactivation of tumor suppressor genes, B-lineage cancer cells carrying the same complete V(D)J or incomplete DJ rearrangement unlimitedly multiply with possible subclone characteristics caused by ongoing SHM or ongoing V(D)J recombination, respectively [40][41][42]. Given that the rearranged IG gene is unique and the quantification of these specific sequences will dramatically increase to a level far beyond the background of the normal IG gene repertoire when malignant cells proliferate, it is convincing and feasible to consider the IG V(D)J rearrangement pattern as an alternative for both clonality assessment of diagnosis and targets of MRD monitoring.…”

Genetic Profiling in Children With Acute Lymphoblastic Leukemia Referred for Allogeneic Hematopoietic Stem Cell Transplantation

“…Some gene mutations or rearrangements are responsible for the development of aggressive and treatment-resistant types of leukemia. [12][13][14][15][16] Patients with ALL should be screened for the following genetic aberrations: deletion of IKZF1, PAX5, CDKN2A, CDKN2B, P2RY8-CRLF2, EGR, rearrangements of ABL1, ABL2, CSF1R, PDGFRbeta, IGH, CRLF2, EPOR, NTRK3, BCR-ABL1, AFF1 (mll), AFF1-KMT2A (MLL-AF4), ETV6-RUNX1 (TEL-AML1), TCF3, mutation of JAK2, as well as hypo-or hyperdiploidy. 9 Detection of the genetic background that contributes to poor prognosis remains a challenge and may be a basis for developing new therapeutic targets.…”