BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas

• Published in: Haematologica (Roma) Vol. 97; no. 4; pp. 595 - 598
• Main Authors: QINGGUO YAN, YUANXUE HUANG, WATKINS, A. James, KOCIALKOWSKI, Sylvia, NAIYAN ZENG, HAMOUDI, Rifat A, ISAACSON, Peter G, DE LEVAL, Laurence, WOTHERSPOON, Andrew, DU, Ming-Qing
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.04.2012
• Subjects: Biological and medical sciences; CARD Signaling Adaptor Proteins - genetics; Chromosome Deletion; Chromosomes, Human, Pair 7; DNA-Binding Proteins - genetics; Guanylate Cyclase - genetics; Hematologic and hematopoietic diseases; Humans; Intracellular Signaling Peptides and Proteins - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell, Marginal Zone - genetics; Lymphoma, B-Cell, Marginal Zone - metabolism; Medical sciences; Mutation; Myeloid Differentiation Factor 88 - genetics; Nuclear Proteins - genetics; Original and Brief Reports; Receptors, Antigen, B-Cell - metabolism; Signal Transduction; Splenic Neoplasms - genetics; Splenic Neoplasms - metabolism; Toll-Like Receptors - metabolism; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Suppressor Protein p53 - genetics; Spleen; MyD88 adaptor protein; Targeting; Hematology; Marginal zone lymphoma; Toll like receptor; Malignant hemopathy; SMZL; Somatic mutation; Chronic; Signaling pathway; Lymphoproliferative syndrome; C-Onc gene; Genetics; CARD11; MYD88; Cancer; A20
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2011.054080

The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-κB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-κB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-κB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.