AUTHOR=Perez-Chacon Gema , Zapata Juan M. 

TITLE=The Traf2DNxBCL2-tg Mouse Model of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Recapitulates the Biased IGHV Gene Usage, Stereotypy, and Antigen-Specific HCDR3 Selection of Its Human Counterpart

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.627602

DOI=10.3389/fimmu.2021.627602

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Traf2</italic>DN/<italic>BCL2</italic> double-transgenic (tg, <sup>+/+</sup>) 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 <italic>Traf2</italic>DN/<italic>BCL2</italic>-tg<sup>+/+</sup> 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 <italic>Traf2</italic>DN/<italic>BCL2</italic>-tg<sup>-/-</sup> (wild-type), <sup>-/+</sup> (<italic>BCL2</italic> single-tg) and <sup>+/-</sup> (<italic>Traf2DN</italic>DN single-tg) littermates showed the expression of various IGHV gene subgroups, the CLL/SLL expanded clones from the <italic>Traf2</italic>DN/<italic>BCL2</italic>-tg<sup>+/+</sup> (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 <italic>Traf2</italic>DN/<italic>BCL2</italic>-tg<sup>+/+</sup> mice and its human counterpart.</p>