Molecular Evidence for Antigen Drive in the Natural History of Mantle Cell Lymphoma

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Authors	XOCHELLI Aliki SUTTON Lesley-Ann AGATHANGELIDIS Andreas STALIKA Evangelia KARYPIDOU Maria MARANTIDOU Fotini LOPEZ Alba Navarro PAPADOPOULOS Giorgos ŠUPÍKOVÁ Jana GROENEN Patricia BOUDJOGRA Myriam SUNDSTROM Christer PONZONI Maurilio SKUHROVÁ FRANCOVÁ Hana ANAGNOSTOPOULOS Achilles POSPÍŠILOVÁ Šárka PAPADAKI Theodora TZOVARAS Dimitris GHIA Paolo POTT Christiane DAVI Frederic CAMPO Elias ROSENQUIST Richard HADZIDIMITRIOU Anastasia BELESSI Chrysoula STAMATOPOULOS Kostas
Year of publication	2015
Type	Article in Periodical
Magazine / Source	AMERICAN JOURNAL OF PATHOLOGY
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://www.sciencedirect.com/science/article/pii/S0002944015001388
Doi	http://dx.doi.org/10.1016/j.ajpath.2015.02.006
Field	Oncology and hematology
Keywords	CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; V-H GENES; CLASS-SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; B-CELLS; IMMUNOGLOBULIN RECEPTORS; CLONAL EVOLUTION; SPLICE VARIANTS; MUTATION STATUS
Attached files	ZVV_2015_116_1318372_Molecular_Evidence.pdf
Description	To further our understanding about antigen involvement in mantle cell Lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-Delta E4a, AID-Delta E) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-Length transcript levels were significantly associated (P < 0.001) with Lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.
Related projects:	CEITEC - Central European Institute of Technology Molekulární charakterizace B buněčných receptorů a jejich vztah k evoluci genetických změn u chronické lymfocytární leukémie Expression and function of activation-induced cytidine deaminase splice variants in normal B cell physiology and chronic lymphocytic leukemia