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

Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla Heavican, Cynthia M. Lachel, Jiayu Yu, Roberto Ferro, Nanees Eldorghamy, Timothy C. Greiner, Julie Vose, Dennis D. Weisenburger, Randy D. Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M. Rimsza, Elaine S. Jaffe, Rita M. BrazielReiner Siebert, Rodney R. Miles, Sandeep Dave, Anupama Reddy, Jan Delabie, Louis M. Staudt, Joo Y. Song, Timothy W. McKeithan, Kai Fu, Michael Green, Wing C. Chan, Javeed Iqbal

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressivelymphomas 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 MYCARF- 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 (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 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 BCL2 and MYC translocations and/or KMT2D(MLL2)mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92'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 andtheBCR→PI3Kor NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

Original languageEnglish (US)
Pages (from-to)1819-1831
Number of pages13
JournalBlood
Volume130
Issue number16
DOIs
StatePublished - Oct 19 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Bouska, A., Bi, C., Lone, W., Zhang, W., Kedwaii, A., Heavican, T., Lachel, C. M., Yu, J., Ferro, R., Eldorghamy, N., Greiner, T. C., Vose, J., Weisenburger, D. D., Gascoyne, R. D., Rosenwald, A., Ott, G., Campo, E., Rimsza, L. M., Jaffe, E. S., ... Iqbal, J. (2017). Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: Genomic features and potential therapeutic targets. Blood, 130(16), 1819-1831. https://doi.org/10.1182/blood-2017-02-767335