Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets

Abstract

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway ( and ) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had translocation and mutation and elevated mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both and translocations and/or () mutation. Gain/amplification of and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

Understanding lymphoma molecular complexity

“…Based on the latter finding and the knowledge that targets of miR17;92 include FCGR2B, modulating BTK function via SHIP and PLCg, the authors postulated sensitivity to BTK inhibitors. 1 This assumption was supported by growth inhibition by ibrutinib in the 6 BL cell lines tested in a time-and dose-dependent manner. 1 Accordingly, patients with molecular BL and MIR17HG amplification (which is characterized by an unfavorable prognosis) might benefit from the use of BTK inhibitors.…”

“…1 This study has several practical implications regarding (1) the concept of the pathological entity, (2) the understanding of the different mechanisms at work in patients who apparently have the same disease, and (3) the impact that a comprehensive molecular approach can have on the identification of novel therapeutic targets.…”

“…The study by Bouska et al represents an excellent example of the way in which an integrated molecular approach can contribute to the better subclassification of malignant lymphomas belonging to the same category, as well as to a better understanding of their pathogenesis and novel targeted therapy discovery. 1 It is clear that only the blend of information produced by the application of different technologies to the study of a given hematolymphoid tumor (as exemplified in the figure) can actually promote translational research and precision medicine with benefit for the patient. Virtually all pediatric ALL protocols use genetics and treatment response to direct therapy, whereas the majority of adult protocols are limited to segregating patients on the basis of the presence or absence of the Philadelphia chromosome (Ph), which harbors the BCR-ABL1 fusion gene.…”

Molecular characteristics of terminal deoxynucleotidyl transferase negative precursor B‐cell phenotype Burkitt leukemia with IGH‐MYC rearrangement

“…8 Among cases with a precursor B-cell immunophenotype, [9][10][11][12] only one TdT-negative cases has been reported. The frequencies of gene mutation detected in cases 1 and 2 were compared with previous reports of Burkitt lymphoma/leukemia 19,20,22 [Color figure can be viewed at wileyonlinelibrary.com] as an L3/BL-like morphology, immunophenotype of blasts, and the presence of IGH-MYC rearrangement. Although heterogeneous in clinical features, both cases shared some similarities, such F I G U R E 2 Summary of singlenucleotide variants and insertion/deletion identified by whole exome sequencing.…”

Detection of a deletion at 22q11 locus involving ZNF280A/ZNF280B/PRAME/GGTLC2 in B‐cell malignancies: simply a consequence of an immunoglobulin lambda light chain rearrangement

“…However, the data above and the previous analysis (Mraz et al , ) shows that ZNF280(A/B)/PRAME/GGTLC2 , unlike miR‐650 , do not play a role in malignant B cell biology, their deletion is simply reflecting the consequences of a physiological IGL rearrangement and the position of these genes between the V subgenes. The deletions in the 22q11 locus have been repeatedly described in CLL and B cell lymphomas (Gunn et al , ; Kolquist et al , ; Bouska et al , ), however, we would like to suggest that this deletion should be ignored in B cell malignancies, because it has no consequence for B cell biology or aggressiveness of malignant B cells.…”