期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.627602
关键词
TRAF2; BCL2; chronic lymphocytic leukemia; CLL; small lymphocytic lymphoma; IGHV; BCR stereotipy
类别
资金
- Agencia Estatal de Investigacion [PID2019-110405RB-I00/AEI/10.13039/501100011033]
- Instituto de Salud Carlos III [PI16/000895]
- CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)
- FEDER funds
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) is a heterogeneous disease with at least two subtypes, characterized by specific IGHV gene subgroup usage and the existence of stereotyped B-cell receptors. The study on Traf2DN/BCL2-tg(+/+) mice shows remarkable similarities with human CLL/SLL, highlighting the importance of antigen exposure in malignant transformation and clone expansion.
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) is a heterogeneous disease consisting of at least two separate subtypes, based on the mutation status of the immunoglobulin heavy chain variable gene (IGHV) sequence. Exposure to antigens seems to play a role in malignant transformation and in the selection and expansion of more aggressive CLL clones. Furthermore, a biased usage of particular IGHV gene subgroups and the existence of stereotyped B-cell receptors (BCRs) are distinctive characteristics of human CLL. We have previously described that Traf2DN/BCL2 double-transgenic (tg, (+/+)) mice develop CLL/SLL with high incidence with aging. In this model, TNF-Receptor Associated Factor (TRAF)-2 deficiency cooperates with B cell lymphoma (BCL)-2 in promoting CLL/SLL in mice by specifically enforcing marginal zone (MZ) B cell differentiation and rendering B cells independent of BAFF for survival. In this report, we have performed the sequencing of the IGHV-D-J rearrangements of B cell clones from the Traf2DN/BCL2-tg(+/+) mice with CLL/SLL. The results indicate that these mice develop oligoclonal and monoclonal B cell expansions. Allotransplantation of the oligoclonal populations into immunodeficient mice resulted in the preferential expansion of one of the parental clones. The analysis of the IGHV sequences indicated that 15% were mutated (M) and 85% unmutated (UM). Furthermore, while the Traf2DN/BCL2-tg(-/-) (wild-type), (-/+) (BCL2 single-tg) and (+/-) (Traf2DNDN single-tg) littermates showed the expression of various IGHV gene subgroups, the CLL/SLL expanded clones from the Traf2DN/BCL2-tg(+/+) (double-transgenic) mice showed a more restricted IGHV gene subgroup usage and an overrepresentation of particular IGHV genes. In addition, the HCDR3-encoded protein sequence indicates the existence of stereotyped immunoglobulin (Ig) in the BCRs and strong similarities with BCR recognizing autoantigens and pathogen-associated antigens. Altogether, these results highlight the remarkable similarities between the CLL/SLL developed by the Traf2DN/BCL2-tg(+/+) mice and its human counterpart.
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