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.

Gema Perez-Chacon,Juan M Zapata

doi:10.3389/fimmu.2021.627602

Abstract

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.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world
The results presented underscore the similarities between the CLL/small lymphocytic lymphoma (SLL) developed by the Traf2DNxBCL2-tg+/+ mice and the CLL developed by human patients
Compared to other CLL mouse models, such as the Eμ-TCL-1-tg [28] and the MDR−/− and the miR-15a/16-1−/− [32] that only generate UM-CLL clones, the CLL/SLL developed by the Traf2DNxBCL2-tg+/+ mice produce both UM- and M-CLL/SLL clones, similar to human CLL, albeit a vast majority of them are UM

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. It is well established that CLL is a heterogeneous disease consisting of at least two separate subtypes, based on phenotypic and clinical behavior. 55% of CLL patients have mutated (M) immunoglobulin heavy chain variable (IGHV) genes [4,5,6], which have a better prognosis than patients with unmutated (UM)- IGHV genes [6,7,8]. According to phenotypic analysis and gene expression profiling both M- and UM-CLL are antigen-experienced B cells [9, 10]. The differences in clinical outcome and biological characteristics between CLL patients with M- and UM-IGHV genes could be related to distinct differences in mutation incidence and distribution reflecting specific underlying mutagenic mechanisms between these two groups [11]. M- and UM-CLL show differences in BCR reactivity profile [12] and signaling [13]

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Results

Conclusion