Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center.
The simultaneous occurrence of a Hodgkin lymphoma (HL) and a non-Hodgkin lymphoma (NHL) is a rare event, and single cell analyses of such composite lymphomas revealed that NHL and Hodgkin/Reed-Sternberg (HRS) tumor cells are frequently descendants of the same tumor clone precursors. Here we present a composite lymphoma consisting of a mantle cell lymphoma (MCL) and an HL with EBV- and EBV+ HRS cells. Analysis of rearranged V genes of single cells revealed a clonal relationship between MCL and HL tumor cells. Although V gene rearrangements of the MCL were unmutated, mutations were observed in HRS cells. Besides mutations shared by all HRS cells, the EBV+ HRS cells carried identical additional mutations. These findings show that both lymphomas derive from a common precursor, most likely a pre germinal center (GC) B cell that already carried some transforming event(s). However, the presence of mutations in the V genes of the HRS cells further corroborates the importance of the GC reaction for the pathogenesis of HL. Importantly, the finding that only a subclone of the HRS clone, defined by a particular mutation pattern, was EBV infected represents a strong indication that EBV infection of the HRS cell precursor happened in the GC.
Department of Pathology, University of Frankfurt, Germany.
Marianne
M
Tinguely
Richard
R
Rosenquist
Christer
C
Sundström
Rose-Marie
RM
Amini
Ralf
R
Küppers
Martin-Leo
ML
Hansmann
Andreas
A
Bräuninger
D000328:Adult; D000818:Animals; D002999:Clone Cells; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000473:pathology*; D015321:Gene Rearrangement; D018858:Germinal Center / Q000473:pathology / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D006689:Hodgkin Disease / Q000473:pathology* / Q000821:virology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017403:In Situ Hybridization; D020522:Lymphoma, Mantle-Cell / Q000473:pathology* / Q000821:virology; D008297:Male; D008846:Micromanipulation; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000032:analysis; D016539:Reed-Sternberg Cells / Q000473:pathology* / Q000821:virology; D012269:Ribosomal Proteins
D007135:Immunoglobulin Variable Region; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; C067169:RPL22 protein, human