Molecular histogenesis of posttransplantation lymphoproliferative disorders.
Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.
Capello
Daniela
D
Hematology Unit, Department of Medical Sciences & Interdisciplinary Research Center on Autoimmune Diseases, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy.
Cerri
Michaela
M
Muti
Giuliana
G
Berra
Eva
E
Oreste
Pierluigi
P
Deambrogi
Clara
C
Rossi
Davide
D
Dotti
Giampietro
G
Conconi
Annarita
A
Viganò
Mario
M
Magrini
Umberto
U
Ippoliti
Giovanbattista
G
Morra
Enrica
E
Gloghini
Annunziata
A
Rambaldi
Alessandro
A
Paulli
Marco
M
Carbone
Antonino
A
Gaidano
Gianluca
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D004854:Herpesvirus 4, Human; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016377:Organ Transplantation / Q000009:adverse effects*; D012189:Retrospective Studies; D027041:Somatic Hypermutation, Immunoglobulin; D014763:Viral Matrix Proteins / Q000502:physiology
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins