Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

Jonathan Reichel, Amy Chadburn, Paul G. Rubinstein, Lisa Giulino-Roth, Wayne Tam, Yifang Liu, Rafael Gaiolla, Kenneth Eng, Joshua Brody, Giorgio Inghirami, Carmelo Carlo-Stella, Armando Santoro, Daoud Rahal, Jennifer Totonchy, Olivier Elemento, Ethel Cesarman, Mikhail Roshal

Research output: Contribution to journalArticlepeer-review

Abstract

Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. ßoglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2Mprotein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define amajor subset of cHL that hasmore uniformclinical andmorphologic features.

Original languageEnglish
Pages (from-to)1061-1072
Number of pages12
JournalBlood
Volume125
Issue number7
DOIs
Publication statusPublished - Feb 12 2015

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

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