Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia

Gawad, Charles; Pépin, François; Carlton, Victoria; Klinger, Mark; Logan, Aaron C.; Miklos, David B.; Faham, Malek; Dahl, Gary V.; Lacayo, Norman J.

doi:10.1182/blood-2012-05-429811

Cited by 116 publications

(123 citation statements)

References 41 publications

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“…We found, on average, 7.4 distinct V H DJ H junctions per thousand mapped paired-end reads per sample (Table 1). However, the number of unique rearrangements per sample ranged broadly from 0.5 to 27.1 per thousand mapped paired-end reads, indicating high VDJ heterogeneity within DLBCL samples, similar to what has been reported in acute B lymphoblastic leukemia (B-ALL) [10]. There was no significant difference in number of unique rearrangements per thousand mapped paired-end reads between the paired diagnosis and relapse samples (6.6 ± 7.5 versus 6.2 ± 6.9, P = 0.85, paired t-test; or P = 0.80, Wilcoxon matched pairs test; Figure S2 in Additional file 3).…”

Section: Deep Vdj Sequencing Revealing Clonal Heterogeneity Of Dlbclmentioning

confidence: 68%

“…To exhaustively catalog the V H DJ H repertoires of the tumor samples, we adapted next-generation sequencing technology to sequence the IgVDJ rearrangements in great depth. This approach has been successfully used in other studies to examine human antibody repertoires [12,34,35], assess clonal heterogeneity in B-ALL or chronic lymphocytic leukemia [10,36,37], or monitor minimal residual disease in chronic lymphocytic leukemia [38]. We observed a wide range of VDJ heterogeneity within diagnosis DLBCL samples, but no significant differences in this between the paired diagnosis and relapse tumors, suggesting that tumor heterogeneity was preserved after disease progression due to either the incomplete eradication of the diagnosis tumor or ongoing VDJ rearrangement during relapse.…”

Section: Discussionmentioning

confidence: 99%

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Deep-sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Jiang¹,

Redmond²,

Nie³

et al. 2014

Genome Biol

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Background: Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas -VDJ recombination and somatic hypermutation -to address this question. Results: We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events. Conclusions: Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.

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Section: Deep Vdj Sequencing Revealing Clonal Heterogeneity Of Dlbclmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Deep-sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Jiang¹,

Redmond²,

Nie³

et al. 2014

Genome Biol

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“…At the bulk level, three of the six patients had no evidence of VH replacement, which was recently shown to occur at higher levels than previously detectable in some ALL samples using immune repertoire sequencing (23). However, patient 5 had two distinct IgH sequences identified in the bulk samples, and single-cell interrogations detected both sequences in most cells, suggesting that both IgH alleles had been rearranged.…”

Section: Resultsmentioning

confidence: 91%

Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics

Gawad

Koh

Quake

2014

Proc. Natl. Acad. Sci. U.S.A.

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284

323

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Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority of patients. Evaluation of intraclonal mutation patterns identified clone-specific punctuated cytosine mutagenesis events, showed that most structural variants are acquired before SNVs, determined that KRAS mutations occur late in disease development but are not sufficient for clonal dominance, and identified clones within the same patient that are arrested at varied stages in B-cell development. Taken together, these data order the sequence of genetic events that underlie childhood ALL and provide a framework for understanding the development of the disease at single-cell resolution.single-cell genomics | acute lymphoblastic leukemia | intratumor heterogeneity | clonal evolution | cytosine mutagenesis A more comprehensive understanding of how malignancies develop could facilitate the rational development of novel anticancer treatment and prevention strategies. Large projects that aim to comprehensively characterize somatic mutations in cancer samples have cataloged many of the recurrent genomic lesions in a wide variety of tumors (1). However, these studies do not measure the correlated cooccurrence of genomic lesions between different cells, which is required for understanding the clonal structure of a tumor as well as for rigorously determining temporal ordering of mutation acquisition. Other studies have provided some temporal resolution of mutation segregation patterns from diagnosis to disease recurrence, allowing for post hoc inference of intratumor clonal heterogeneity at diagnosis (2-5). However, approaches that rely on mutant allele frequencies to determine clonal structure require multiple samples from the same patient and are unable to resolve clones with mutations present at similar frequencies, which is a prerequisite to unambiguously determine the clonal structure and delineate the evolution of the disease (3-5). In principle, single cell genomics provides the most rigorous method to determine the clonal heterogeneity of tumors; as discussed below, there have been recent advances in this approach, but technical limitations have until now prevented it from fully addressing the questions of interest.Studies of pediatric acute lymphoblastic leukemias (ALL) have provided a limited ordering of the genetic events that underlie childhood leukemogenesis by studying prediagnostic samples. For example, ETV6 -RUNX1 translocations, which occur in about a third of patients under 10 y of age, have been shown to occur in utero by tracking the translocation back to neonatal blood spots (6, 7). In addition, a recent report ...

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“…112,113 HTS IG-TR can also detect clonal evolution of IG-TR rearrangements 114 and provide insight into the background repertoire of B and T cells. Overall, HTS can speed up the process of molecular MRD quantification and provide results at early time points of the treatment, which has not been possible before because of the time-consuming ASO-RQ-PCR preparations.…”

Section: High-throughput Sequencing Of Ig-tcr Targets (Dna Level)mentioning

confidence: 99%

Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies

Dongen

Velden

Brüggemann

et al. 2015

Blood

416

384

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Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10−4), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10−4, whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages.

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Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia

Cited by 116 publications

References 41 publications

Deep-sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Deep-sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics

Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies

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