Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

Haematologica. 2021 Apr 1;106(4):1120-1128. doi: 10.3324/haematol.2020.251579.

Abstract

Plasmablastic lymphoma mutational profile is undescribed. Here we performed a targeted exonic NGS analysis of 30 plasmablastic lymphoma cases with a B cell lymphoma dedicated panel and FISH for the detection of MYC rearrangements. A complete phenotyping of the neoplastic and microenvironment cell populations was also performed. We have identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and 3 cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in EBV positive disease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed consistent MYC expression, higher in cases with MYC rearrangements together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironment populations were heterogeneous and unrelated with EBV, with an enrichment of Tumor Associated Macrophages (TAM) and PD1 positive T cells. PD-L1 was expressed in all cases in the TAM population but only in 5 cases in the neoplastic cells (4 out of 14 EBV positive cases). HLA expression was absent in the majority of PBL cases. In summary, Plasmablastic lymphoma mutational profile is heterogeneous and related with EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV positive disease. An enrichment in TAM and PD1 reactive T lymphocytes is found in the microenvironment of PBL cases, that express PD-L1 in the neoplastic cells in a fraction of cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis
  • Epstein-Barr Virus Infections*
  • Humans
  • Plasmablastic Lymphoma* / diagnosis
  • Plasmablastic Lymphoma* / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • STAT3 Transcription Factor / genetics
  • Translocation, Genetic
  • Tumor Microenvironment / genetics

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • STAT3 Transcription Factor
  • STAT3 protein, human

Grant support

Funding: This study was supported by grants from MINECO (PI16/1397, SMM, Principal Investigator) and IDIVAL (NEXTVAL 15/09, SMM, Principal Investigator). NMM was supported by Asociación Española contra el Cancer (AECC).