Abstract IA011: Ccnd1 initiates mantle cell lymphoma–like disease and cooperates with Sox11 expression and loss of Atm/Trp53

Abstract

Mantle cell lymphoma (MCL) is characterized by t(11;14)-driven Cyclin D1 (encoded by CCND1) overexpression and recurrent alterations affecting SOX11, ATM, and TP53. Yet, how these lesions cooperate to drive lymphomagenesis in vivo remains incompletely understood. Here, we established conditional autochthonous genetically engineered mouse models integrating CD19 Cre -mediated B cell–specific overexpression of Ccnd1 and Sox11, and loss of Atm and Trp53 to reflect MCL hallmarks and investigate its evolution. Ccnd1 overexpression led to lymphoproliferative disease with long latency that progressed to systemic lymphoma, supporting a role as an initiating lesion. Additional loss of Atm and Trp53 markedly accelerated disease onset and lymphoma penetrance. Sox11 overexpression alone less frequently resulted in lymphoma, but combination with Ccnd1 overexpression increased disease penetrance and accelerated lymphomagenesis, further indicating cooperative effects. Across genotypes, mice developed systemic lymphoma involving lymphoid and non-lymphoid tissues, including bone marrow, blood, liver, and gastrointestinal tract. Tumors displayed a canonical MCL-like immunophenotype characterized by expansion of CD19+ B cells with aberrant CD5 expression, absence of CD23, and an IgM+, non–class-switched state. Blinded histopathological evaluation by an expert hematopathologist confirmed morphologic and immunophenotypic features consistent with human MCL. B cell receptor sequencing revealed oligo- to monoclonal disease lacking somatic hypermutation and class-switch recombination, consistent with a germinal center–inexperienced origin. Additionally, whole-exome sequencing showed acquired genetic alterations commonly observed in human MCL, including non-synonymous mutations in Trp53 and Map3k14, as well as copy number variations affecting Card11 and Cdkn2a. Transcriptome analyses supported Sox11-associated transcriptional programs and suppression of germinal center–associated genes. Strikingly, primary lymphomas were readily transplantable in mice with high engraftment rates and serial passaging capacity, enabling their use in in vivo functional and therapeutic studies. Together, these findings support that Ccnd1 overexpression initiates a pre–germinal center B cell state that undergoes clonal evolution and is shaped by additional genetic lesions to drive overt lymphoma. These MCL in vivo models provide a basis for studying disease biology and for evaluating therapeutic approaches in genetically defined settings in an immunocompetent environment.